WO2023065475A1 - 晶型预测方法、装置及电子设备 - Google Patents
晶型预测方法、装置及电子设备 Download PDFInfo
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Definitions
- the present application relates to the technical field of crystal form prediction, in particular to a crystal form prediction method, device and electronic equipment.
- the same substance has two or more spatial arrangements and unit cell parameters, and the phenomenon of forming multiple crystal forms is called polymorphism.
- Years of research have found that different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, and bioavailability, which affect the stability, bioavailability, and efficacy of the drug. Therefore, it has become an indispensable link in the standard drug development process to obtain relatively stable pharmaceutical crystal forms through experimental screening of polymorphic drugs.
- CSP crystal structure prediction
- the present application provides a crystal form prediction method, device and electronic equipment, which can reduce the difficulty of crystal form prediction, shorten the prediction time, and improve the prediction efficiency.
- the first aspect of the present application provides a crystal form prediction method, which includes:
- the acquisition of diffraction images corresponding to a plurality of sample particles of the target sample includes:
- a plurality of diffraction images of a plurality of sample particles of a target sample within a preset angle range in a shooting environment at a preset temperature are respectively obtained by electron diffraction.
- the generating the initial crystal form of the target sample according to the parameter information obtained in each of the diffraction images includes:
- the initial crystal form is corrected according to the known molecular structure of the target sample to obtain the corrected crystal form, including:
- the method also includes:
- the initial crystal form is discarded, and sample particles are reacquired for electron diffraction to generate a new initial crystal form.
- the method further includes: if the molecular structure error rate of the initial crystal form is less than or equal to a preset ratio threshold, adopting the initial crystal form.
- the prediction of the crystal form according to the corrected crystal form to obtain the predicted crystal form of the target sample includes:
- the missing atoms in the modified crystal form are predicted, and the predicted crystal form whose ground state energy conforms to the preset rules is obtained.
- the acquiring virtual atom information in the Voronoi diagram includes:
- the atomic coordinates in the corrected crystal form are used as discrete point coordinates and the Voronoi diagram is generated, it includes:
- each of the vertex coordinates and the discrete point coordinates calculate the linear distance between each of the vertex coordinates and the nearest discrete point coordinates
- the prediction of missing atoms in the corrected crystal form according to the known molecular structure of the target sample and the virtual atom information includes:
- the atomic species and the corresponding atomic center coordinates of the known molecular structure in the target sample and the central coordinates and corresponding virtual atom radii of each virtual atom in the virtual atom information set are used as the input structure for CSP crystal form prediction, and Correct the missing atoms in the crystal form for prediction.
- the prediction of missing atoms in the corrected crystal form to obtain a predicted crystal form whose ground state energy complies with preset rules includes:
- the preliminary predicted crystal form with the lowest ground state energy is selected as the predicted crystal form.
- the method also includes:
- Verifying the predicted crystal form wherein, when the residual factor between the simulated structure factor and the experimental structure factor of the predicted crystal form is less than or equal to a preset value, it is determined that the verification of the predicted crystal form is passed.
- the second aspect of the present application provides a crystal form prediction device, which includes:
- An image acquisition module configured to acquire diffraction images corresponding to multiple sample particles of the target sample
- a crystal form generating module configured to generate the initial crystal form of the target sample according to the parameter information obtained in each of the diffraction images
- a crystal form correction module configured to correct the initial crystal form according to the known molecular structure of the target sample to obtain the corrected crystal form
- the crystal form prediction module is used to predict the crystal form according to the modified crystal form, and obtain the predicted crystal form of the target sample.
- the device also includes:
- a parameter processing module configured to perform index processing on each of the diffraction images to obtain parameter information corresponding to the target sample; combine parameter information of multiple target samples to obtain parameter combination information; wherein, the The number of diffraction points in the parameter merging information is not less than a preset number threshold.
- the device also includes:
- the crystal form verification module is used to verify the predicted crystal form; wherein, when the residual factor between the simulated structure factor and the experimental structure factor of the predicted crystal form is less than or equal to a preset value, the predicted crystal form is determined Verification passed.
- the crystal form correction module is used to delete wrong atoms different from known atoms in the initial crystal form and delete the initial crystal form according to the known atoms and known groups of the target sample.
- the wrong group in the crystal form is different from the known group, and the corresponding modified crystal form is obtained.
- the crystal form prediction module is also used to use the atomic coordinates in the corrected crystal form as discrete point coordinates to generate a Voronoi diagram; obtain virtual atom information in the Voronoi diagram ; According to the known molecular structure and virtual atom information of the target sample, predict the missing atoms in the modified crystal form, and obtain the predicted crystal form whose ground state energy conforms to the preset rules.
- the third aspect of the present application provides an electronic device, including:
- a memory on which is stored executable code that, when executed by the processor, causes the processor to perform the method as described above.
- a fourth aspect of the present application provides a computer-readable storage medium, on which executable code is stored, and when the executable code is executed by a processor of an electronic device, the processor is caused to execute the above-mentioned method.
- the crystal form prediction method provided in the embodiment of the present application, first obtain the diffraction image of multiple sample particles of the target sample, and then obtain the required parameter information through the diffraction image to obtain the initial crystal form, and then correct the initial crystal form To obtain the corrected crystal form, and finally predict the crystal form based on the corrected crystal form to obtain the predicted crystal form of the target sample.
- the prediction method of this application can pre-eliminate the interference of some wrong crystal forms, so as to make targeted predictions on the basis of corrected crystal forms. The prediction difficulty is reduced, the prediction time is shortened, and the crystal form prediction efficiency is improved.
- the diffraction image of the sample particle is first obtained through the image acquisition module, and then the required parameter combination information is obtained through the parameter processing module according to the diffraction image, and the crystal form generation module obtains the initial crystal form according to the parameter combination information.
- the crystal form correction module corrects the initial crystal form to obtain the corrected crystal form
- the crystal form prediction module performs crystal form prediction on the basis of the corrected crystal form to obtain the predicted crystal form
- the crystal form verification module verifies the predicted crystal form type of credibility.
- the prediction method of this application can pre-eliminate the interference of some wrong crystal forms, so as to make targeted predictions on the basis of corrected crystal forms. It reduces the difficulty of prediction, shortens the prediction time, and improves the efficiency of crystal form prediction; in addition, compared with X-ray single crystal diffraction, the device of the present application directly uses electron diffraction to reduce the requirements for sample quality, reduce the cost of cultivating samples, and shorten The overall crystal form prediction time improves prediction efficiency.
- Fig. 1 is a schematic flow chart of the crystal form prediction method shown in the embodiment of the present application.
- Fig. 2 is another schematic flowchart of the crystal form prediction method shown in the embodiment of the present application.
- Fig. 3 is a schematic structural diagram of a crystal form prediction device shown in an embodiment of the present application.
- Fig. 4 is another structural schematic diagram of the crystal form prediction device shown in the embodiment of the present application.
- FIG. 5 is a schematic structural diagram of an electronic device shown in an embodiment of the present application.
- first, second, third and so on may be used in this application to describe various information, such information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another.
- first information may also be called second information, and similarly, second information may also be called first information.
- second information may also be called first information.
- a feature defined as “first” and “second” may explicitly or implicitly include one or more of these features.
- “plurality” means two or more, unless otherwise specifically defined.
- the embodiment of the present application provides a crystal form prediction method, which can reduce the difficulty of prediction, shorten the prediction time, and improve the prediction efficiency.
- Fig. 1 is a schematic flow chart of the crystal form prediction method shown in the embodiment of the present application.
- the crystal form prediction method of an embodiment of the present application includes:
- Step S110 acquiring diffraction images corresponding to a plurality of sample particles of the target sample.
- the target sample is made into a powder form in advance, so as to obtain a plurality of sample particles.
- the diffraction image corresponding to each sample particle can be obtained by electron diffraction.
- the corresponding diffraction images obtained by shooting a single sample particle at different angles can be obtained, so as to obtain the diffraction images of the sample particle at multiple angles, so that subsequent steps can extract parameter information at different angles.
- Step S120 generating the initial crystal form of the target sample according to the parameter information obtained from the diffraction image of each sample particle.
- the parameter information includes unit cell parameters and diffraction intensities of diffraction points.
- the corresponding unit cell parameters can be obtained by calibrating the diffraction pattern, for example, the unit cell parameters can include the angle between two intersecting crystal planes and the crystal planes of two adjacent crystal planes spacing etc.
- the unit cell parameters can include the angle between two intersecting crystal planes and the crystal planes of two adjacent crystal planes spacing etc.
- the diffraction intensity of each diffraction point in the diffraction pattern according to the related art.
- a sufficient amount of parameter information can be obtained, and then the initial crystal form can be obtained by analyzing the parameter information according to related technologies. It can be understood that if the constituent elements or groups of crystalline substances are not the same or their structures are different, their diffraction images will show differences in the number of diffraction peaks, angular positions, relative diffraction intensity order and the shape of diffraction peaks. Therefore, according to related technologies, comparative analysis can complete the qualitative identification of the phase composition and structure of the target sample; through the analysis and calculation of the diffraction intensity data of each diffraction point of the sample particle, the quantitative analysis of the phase composition of the target sample can be completed .
- Step S130 correcting the initial crystal form according to the known molecular structure of the target sample to obtain the corrected crystal form.
- the optimal pharmaceutical crystal form of the target sample is unknown, on the premise that the molecular structure of the target sample is known, the known atoms and known Groups, so that the obviously incorrect atoms and groups in the initial crystal form can be deleted, so as to correct the initial crystal form, that is, to obtain the corrected modified crystal form.
- Preliminary correction of the initial crystal form is carried out so that subsequent steps can predict the crystal form of the target sample on the basis of the corrected crystal form, thereby narrowing the prediction range.
- Step S140 predicting the crystal form according to the corrected crystal form to obtain the predicted crystal form of the target sample.
- the predicted crystal form of the target sample can be obtained by inputting the structure of the corrected crystal form.
- the technical solution of the present application first obtains the diffraction images of multiple sample particles of the target sample, and then obtains the required parameter information through the diffraction images to obtain the initial crystal form, and then corrects the initial crystal form To obtain the corrected crystal form, and finally predict the crystal form based on the corrected crystal form to obtain the predicted crystal form of the target sample.
- the prediction method of this application can pre-eliminate the interference of some wrong crystal forms, so as to make targeted predictions on the basis of corrected crystal forms. The prediction difficulty is reduced, the prediction time is shortened, and the crystal form prediction efficiency is improved.
- Fig. 2 is another schematic flowchart of the crystal form prediction method shown in the embodiment of the present application.
- the crystal form prediction method of the present application includes:
- step S210 multiple diffraction images of multiple sample particles of the target sample within a preset angle range in a shooting environment at a preset temperature are respectively acquired by electron diffraction.
- diffraction images of multiple sample particles of a powdery target sample can be obtained by electron diffraction (MicroED). Further, the sample particles can be photographed by an electron microscope, such as a transmission electron microscope, to obtain diffraction images.
- the sample particles and the shooting environment are subjected to freezing treatment in advance, so that the sample particles are placed in the frozen shooting environment for electron diffraction, so as to avoid electrons from destroying the sample particles during the shooting process, thereby ensuring Obtain a diffraction image with ideal shooting effect.
- the preset temperature may be -250°C ⁇ 0°C. For example -250°C to -50°C, -200°C to -50°C or -200°C to -100°C, etc. understandable,
- sample particles at non-freezing temperatures are destroyed by electrons and the obtained diffraction images do not look good.
- a number of powdery sample particles can be evenly dispersed on the grid, and then the grid containing the sample particles is frozen by liquid nitrogen; then the frozen grid is loaded into the sample rod, and the sample The rod is mounted to the TEM in cryo mode, and the frozen sample particles are photographed in cryo mode.
- the sample rod is rotated within a preset angle range at a preset speed to obtain different shooting angles. For example, the sample rod is rotated along the fixed axis within a preset angle range of -60° to 60° at a speed of 0.5° to 1° per second. In one embodiment, the preset angle range may also be -45°-45°, -30-30°, or -10-10°.
- a transmission electron microscope is used to obtain a series of diffraction images at different angles for each sample particle in the freezing mode within a preset angle range.
- X-ray single crystal diffraction requires large-scale quality crystals, but for organic molecules, it is very difficult or even impossible to grow single crystals, that is, it is very difficult to obtain consistent samples.
- electron diffraction is used to act on the powdery target sample, without spending a lot of manpower and material resources to cultivate single crystals.
- Step S220 respectively acquiring and merging the parameter information acquired in the plurality of diffraction images to obtain parameter merging information.
- each diffraction image is indexed to obtain the parameter information corresponding to the sample particle; where the parameter information includes the unit cell parameters and the diffraction intensity of the diffraction point ; Combining parameter information of multiple sample particles to obtain parameter combination information; wherein, the number of diffraction points in the parameter combination information is not less than a preset number threshold.
- indexing processing of crystal diffraction data can be performed according to indexing software in the related art, such as DICVOL software, ipmosflm software, HKL2000 software, XDS software, etc. Indexing software.
- indexing software such as DICVOL software, ipmosflm software, HKL2000 software, XDS software, etc.
- Indexing software corresponding parameter information can be obtained in each diffraction image, and the parameter information includes unit cell parameters and diffraction intensities of diffraction points. Specifically, refer to the description of step S120 , which will not be repeated here.
- indexing based on powder diffraction requires more parameter information to obtain as complete data as possible. Therefore, a series of diffraction images of each sample particle are indexed to obtain the corresponding parameter information of each diffraction image Finally, the parameters are combined to obtain the diffraction intensity of a sufficient number of diffraction points. Wherein, when the number of diffraction points is not less than the preset number threshold, it means that the parameter combination information meets the requirements.
- step S210 to obtain a new diffraction image of the sample particle or a new diffraction image of the original sample particle, so that this step can obtain Sufficient number of diffraction points.
- the preset quantity threshold is adjusted according to target samples with different molecular structures, and target samples with more complex molecular structures need more diffraction points and correspondingly need more diffraction images.
- the information of each parameter can be combined into a set of data by using data combining software in the related art, that is, the combined parameter information can be obtained.
- the data consolidation software can be XSCALE software.
- the generated parameter merging information includes the .hkl file generated by merging the average unit cell parameters calculated by many unit cell parameters and the diffraction intensities of many diffraction points.
- Step S230 analyzing according to the parameter combination information to obtain an initial crystal form; wherein, the molecular structure error rate of the initial crystal form is less than or equal to a preset ratio threshold.
- the parameter combination information after the parameter combination information is obtained, according to the parameter combination information, it can be analyzed according to relevant analysis software to obtain the structure corresponding to the initial crystal form.
- the analysis software can be SHELXT software.
- the initial crystal form After obtaining the initial crystal form, it is necessary to determine the molecular structure error rate of the initial crystal form based on the known molecular structure of the target sample. In one embodiment, if the molecular structure error rate of the initial crystal form is greater than the preset ratio threshold, it means that the structure of the initial crystal form deviates too much from the known molecular structure of the target sample, and the initial crystal form is discarded and obtained again. The sample particles undergo electron diffraction to generate new primary crystal forms. It can be understood that when the structure of the initial crystal form deviates too much from the known molecular structure of the target sample, the initial crystal form is likely to be a wrong crystal form.
- the wrong crystal form is not suitable for the crystal form prediction in the subsequent steps, and then the initial crystal form structure with a large deviation is discarded, and this step needs to be repeated to analyze again to obtain a molecular error rate less than or equal to the preset ratio threshold.
- the initial crystal form or, re-execute step S210 and/or step S220 to obtain new parameter combination information, and then re-analyze the parameter combination information to obtain a molecular structure conforming to the initial crystal form.
- the error rate is less than the preset ratio threshold initial crystal form.
- the molecular structure error rate may be the ratio of the sum of the number of wrong atoms and wrong groups in the molecular structure in the initial crystal form to the sum of the total number of atoms and groups; when the ratio is less than or equal to
- the ratio threshold is preset, it means that the initial crystal form can be adopted and used for prediction, which helps to narrow the range of crystal form prediction.
- Step S240 according to the known atoms and known groups of the sample particles, delete the wrong atoms in the initial crystal form that are different from the known atoms and delete the wrong groups in the initial crystal form that are different from the known groups, and obtain the corresponding modified crystal form.
- the wrong atoms and wrong groups in the initial crystal form that are obviously different from the known molecular structure can be deleted.
- the operation deletion can be performed in the analysis software, and only the atoms and groups that completely match the known molecular structure are retained, so as to obtain the corresponding modified crystal form.
- Step S250 predicting the crystal form according to the corrected crystal form to obtain the predicted crystal form.
- the atomic coordinates in the corrected crystal form are used as discrete point coordinates to generate a Voronoi diagram; the virtual atom information in the Voronoi diagram is obtained; according to the known molecular structure and virtual atom information of the target sample , predict the missing atoms in the corrected crystal form, and obtain the predicted crystal form whose ground state energy conforms to the preset rules.
- the atoms in the modified crystal form can be used as discrete points, and the coordinates of the atoms can be used as the coordinates of the discrete points, and a Voronoi Diagram can be drawn to divide the three-dimensional space of the modified crystal form. Furthermore, if each region of the Voronoi diagram contains a discrete point (ie, an atom), another discrete point will not appear on the edge of each region. Therefore, the vertices where multiple regions intersect in the Voronoi diagram and the space around the vertices that do not contain discrete points are the spaces where atoms do not appear, and these spaces can be used as spaces for virtual atoms. In the Voronoi diagram The coordinates of the vertices of the intersecting parts of the multi-block regions can be used as the corresponding virtual atom center coordinates.
- the information of a single virtual atom may be the center coordinate and radius of the virtual atom, and by obtaining the information of the virtual atom, it is helpful to predict the construction of the intramolecular coordinates of the crystal form.
- the coordinates corresponding to each virtual atom can be obtained by obtaining the coordinates corresponding to each vertex whose straight-line distance from the nearest discrete point is greater than or equal to the preset bond length value. That is to say, only the coordinates of some qualified vertices can be used as the central coordinates of virtual atoms, and the half of the straight-line distance between the vertices and the nearest discrete point is the radius of the corresponding virtual atoms.
- the vertex coordinates of the intersecting areas of each area are calculated and obtained through related technologies; according to the coordinates of each vertex and the coordinates of the discrete points, the distance between the coordinates of each vertex and the coordinates of the nearest discrete point can be calculated.
- the straight-line distance between them; each straight-line distance is compared with the preset key length value, and if the straight-line distance is less than the preset key length value, the corresponding vertex in the Voronoi graph is deleted. That is, the deleted vertices are not used as virtual atoms, and the coordinates of undeleted vertices are used as the center coordinates of virtual atoms.
- the preset bond length value may be 1/2 of the common chemical bond length. Common chemical bond lengths can be 1 to 1.5 Angstrom. In one embodiment, the preset key length may be 0.5 ⁇ 0.75 Angstrom, such as 0.5 Angstrom, 0.6 Angstrom, 0.7 Angstrom or 0.75 Angstrom.
- the undeleted intersecting vertices of each area in the Voronoi graph are used as virtual atoms, and the virtual atom and the nearest discrete point, that is, the straight-line distance between the virtual atom and the nearest atom needs to be as long as the common chemical bond 1/2 approximation, if the straight-line distance between the vertex and the nearest atom is too small, then the vertex is not conducive to the construction of normal molecular structure, that is, the vertex is not suitable as a virtual atom. Therefore, by deleting the vertices whose straight-line distance in the Voronoi graph is less than the preset bond length value, the unsuitable virtual atoms are deleted.
- the remaining vertices are used as the central coordinates of the corresponding virtual atoms, and half of the distance between each vertex and the nearest atom is used as the corresponding Virtual atom radius, get virtual atom information set.
- each virtual atom in the virtual atom information set will serve as an obstacle to construct the predicted crystal form, that is, there will be no atoms of the predicted crystal form in the position where there are virtual atoms, thereby assisting the construction of the predicted crystal form structure.
- the missing atoms in the corrected crystal form are predicted, including: the atomic species of the known molecular structure in the target sample and the corresponding Atomic center coordinates and the center coordinates and corresponding virtual atom radii of each virtual atom in the virtual atom information set are used as the input structure for CSP crystal form prediction, so as to predict the missing atoms in the corrected crystal form.
- the molecular structure of the corrected crystal form is completed according to the predicted missing atoms, and at least one preliminary predicted crystal form is obtained; Preliminary predicted crystal forms are sorted by energy; the preliminary predicted crystal form with the lowest ground state energy is selected as the predicted crystal form. It can be understood that the crystal form prediction of CSP can be performed according to related technologies, and details are not described here.
- the ground state energy of each preliminary predicted crystal form can be obtained, and then the preliminary predicted crystal forms are sorted according to the value of the ground state energy, and the preliminary predicted crystal form with the lowest ground state energy value can be used as Predicted crystal form. It can be understood that the lower the energy value of the ground state, the more stable the crystal form, which can be used as an ideal pharmaceutical crystal form.
- Step S260 verifying the predicted crystal form, and obtaining the predicted crystal form that passed the verification.
- the predicted crystal form can be verified.
- the predicted crystal form is verified; wherein, when the residual factor between the simulated structure factor and the experimental structure factor of the predicted crystal form is less than or equal to a preset value, it is determined that the verification of the predicted crystal form is passed.
- the preset value may be 0.3-0.4, such as 0.3, 0.35 or 0.4.
- the residual factor R1 is calculated according to the following formula (1):
- R1 represents the residual factor
- Fcalc represents the simulated structure factor
- Fobs represents the experimental structure factor
- simulated structure factor Fcalc can be calculated according to the following formula (2):
- i represents the imaginary number unit
- j represents the jth atom in the unit cell
- n represents the total number of atoms in the unit cell of the predicted crystal form
- x, y, z are the fractional coordinates of the atoms in the unit cell of the predicted crystal form
- h, k, l are the Miller indices corresponding to the diffraction points.
- the experimental structure factor is obtained by merging the diffraction intensities of the diffraction points in the above step S220. Specifically, the experimental structure factor can be calculated by referring to the following formula (3).
- hkl is the Miller index corresponding to each diffraction point
- I(hkl) is the diffraction intensity of the diffraction point
- F(hkl) is the experimental structure factor
- the value of the residual factor of the predicted crystal form is less than or equal to the preset value, it means that the structure of the predicted crystal form is correct, that is, the verification is passed.
- the predicted crystal form that has passed the verification is the ideal pharmaceutical crystal form. Otherwise, if the residual factor is greater than the preset value, it means that the verification fails.
- step S250 uses the preliminary predicted crystal form whose ground state energy ranking value of each preliminary predicted crystal form in step S250 is the second lowest as the predicted crystal form, and further repeat this step for verification until the verification is passed, and the verification pass is obtained.
- Predicted crystal form It can be understood that the predicted crystal form that passes the verification is the correct and most stable crystal form.
- the obtained corrected crystal form can be used as the input structure for CSP crystal form prediction as an experimental reference, which effectively reduces the deep influence of sample molecular freedom on CSP crystal form prediction and reduces The difficulty of CSP prediction is reduced; in addition, the reliability of the predicted crystal form is improved by verifying the predicted crystal form, so as to obtain a correct and stable predicted crystal form.
- the crystal form prediction method in this example is not limited to the type of sample.
- the predicted crystal form is obtained by combining electron diffraction with CSP crystal form prediction technology, which reduces the difficulty of sample cultivation and the difficulty of CSP crystal form prediction, and can be obtained. It is an ideal crystal form with high reliability and has promotional value.
- the present application also provides a crystal form prediction device, electronic equipment and corresponding embodiments.
- Fig. 3 is a schematic structural diagram of a crystal form prediction device shown in an embodiment of the present application.
- the crystal form prediction device of the present application includes an image acquisition module 310, a crystal form generation module 320, a crystal form correction module 330 and a crystal form prediction module 340, wherein:
- the image acquisition module 310 is used to acquire diffraction images corresponding to a plurality of sample particles of the target sample.
- the crystal form generation module 320 is used to generate the initial crystal form of the target sample according to the parameter information acquired in each diffraction image.
- the crystal form correction module 330 is used to correct the initial crystal form according to the known molecular structure of the target sample to obtain the corrected crystal form.
- the crystal form prediction module 340 is used to predict the crystal form according to the corrected crystal form, and obtain the predicted crystal form of the target sample.
- Fig. 4 is a schematic structural diagram of a crystal form prediction device shown in an embodiment of the present application.
- the image acquisition module 310 of the present application is used to acquire multiple diffraction images of each sample particle within a preset angle range in a shooting environment at a preset temperature through electron diffraction.
- the device of the present application further includes a parameter processing module 350, which is used to perform index processing on each diffraction image respectively to obtain parameter information corresponding to the sample particles; Parameter information is combined to obtain parameter combination information; wherein, the number of diffraction points in the parameter combination information is not less than a preset number threshold.
- the crystal form generation module 320 is used to analyze according to the combined information of parameters to obtain an initial crystal form; wherein, the molecular structure error rate of the initial crystal form is less than or equal to a preset ratio threshold.
- the initial crystal form is discarded, and sample particles are reacquired for electron diffraction to generate a new initial crystal form.
- the crystal form correction module 330 is used to delete the wrong atoms in the initial crystal form that are different from the known atoms and delete the wrong atoms in the initial crystal form based on the known atoms and known groups of the target sample.
- the wrong group with different known groups can obtain the corresponding corrected crystal form.
- the crystal form prediction module 340 is also used to use the atomic coordinates in the corrected crystal form as discrete point coordinates to generate a Voronoi diagram; obtain virtual atom information in the Voronoi diagram; according to With the known molecular structure and virtual atom information of the target sample, the missing atoms in the corrected crystal form are predicted, and the predicted crystal form with the ground state energy conforming to the preset rules is obtained.
- the crystal form prediction module 340 is also used to complete the molecular structure of the corrected crystal form according to the predicted missing atoms, and obtain at least one preliminary predicted crystal form; perform energy calculation of each preliminary predicted crystal form according to the value of the ground state energy of the preliminary predicted crystal form. Sorting; select the preliminary predicted crystal form with the lowest ground state energy as the predicted crystal form.
- the device of the present application also includes a crystal form verification module 360, which is used to verify the predicted crystal form; wherein, when the simulated structure factor of the predicted crystal form and the experimental structure factor When the residual factor between is less than or equal to the preset value, it is determined that the verification of the predicted crystal form is passed.
- a crystal form verification module 360 which is used to verify the predicted crystal form; wherein, when the simulated structure factor of the predicted crystal form and the experimental structure factor When the residual factor between is less than or equal to the preset value, it is determined that the verification of the predicted crystal form is passed.
- the crystal form prediction device of the present application first obtains the diffraction image of the sample particle through the image acquisition module, and then obtains the required parameter combination information according to the diffraction image through the parameter processing module.
- the crystal form correction module corrects the initial crystal form to obtain the corrected crystal form
- the crystal form prediction module performs crystal form prediction on the basis of the corrected crystal form to obtain the predicted crystal form, and crystal form verification The module validates the reliability of the predicted crystal form.
- the prediction method of this application can pre-eliminate the interference of some wrong crystal forms, so as to make targeted predictions on the basis of corrected crystal forms. It reduces the difficulty of prediction, shortens the prediction time, and improves the efficiency of crystal form prediction; in addition, compared with X-ray single crystal diffraction, the device of the present application directly uses electron diffraction to reduce the requirements for sample quality, reduce the cost of cultivating samples, and shorten The overall crystal form prediction time improves prediction efficiency.
- FIG. 5 is a schematic structural diagram of an electronic device shown in an embodiment of the present application.
- the electronic device 1000 includes a memory 1010 and a processor 1020 .
- the processor 1020 can be a central processing unit (Central Processing Unit, CPU), and can also be other general-purpose processors, digital signal processors (Digital Signal Processor, DSP), application specific integrated circuits (Application Specific Integrated Circuit, ASIC), on-site Field-Programmable Gate Array (FPGA) or other programmable logic devices, discrete gate or transistor logic devices, discrete hardware components, etc.
- a general-purpose processor may be a microprocessor, or the processor may be any conventional processor, or the like.
- the memory 1010 may include various types of storage units such as system memory, read only memory (ROM), and persistent storage.
- the ROM may store static data or instructions required by the processor 1020 or other modules of the computer.
- the persistent storage device may be a readable and writable storage device.
- Persistent storage may be a non-volatile storage device that does not lose stored instructions and data even if the computer is powered off.
- the permanent storage device adopts a large-capacity storage device (such as a magnetic or optical disk, flash memory) as the permanent storage device.
- the permanent storage device may be a removable storage device (such as a floppy disk, an optical drive).
- the system memory can be a readable and writable storage device or a volatile readable and writable storage device, such as dynamic random access memory.
- System memory can store some or all of the instructions and data that the processor needs at runtime.
- the memory 1010 may include any combination of computer-readable storage media, including various types of semiconductor memory chips (such as DRAM, SRAM, SDRAM, flash memory, programmable read-only memory), and magnetic disks and/or optical disks may also be used.
- memory 1010 may include a readable and/or writable removable storage device, such as a compact disc (CD), a read-only digital versatile disc (e.g., DVD-ROM, dual-layer DVD-ROM), Read-only Blu-ray Disc, Super Density Disc, Flash memory card (such as SD card, min SD card, Micro-SD card, etc.), magnetic floppy disk, etc.
- a readable and/or writable removable storage device such as a compact disc (CD), a read-only digital versatile disc (e.g., DVD-ROM, dual-layer DVD-ROM), Read-only Blu-ray Disc, Super Density Disc, Flash memory card (such as SD card, min SD card, Micro-SD card, etc.), magnetic floppy disk, etc.
- Computer-readable storage media do not contain carrier waves and transient electronic signals transmitted by wireless or wire.
- Executable codes are stored in the memory 1010, and when the executable codes are processed by the processor 1020, the processor 1020 can be made to execute part or all of the methods mentioned above.
- the method according to the present application can also be implemented as a computer program or computer program product, which includes computer program code instructions for executing some or all of the steps in the above-mentioned method of the present application.
- the present application may also be implemented as a computer-readable storage medium (or a non-transitory machine-readable storage medium or a machine-readable storage medium), on which executable code (or computer program or computer instruction code) is stored,
- executable code or computer program or computer instruction code
- the processor of the electronic device or server, etc.
- the processor is made to perform part or all of the steps of the above-mentioned method according to the present application.
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Abstract
本申请涉及一种晶型预测方法、装置及电子设备。该方法包括:获取目标样品的多个样品颗粒对应的衍射图像;根据各衍射图像中获取的参数信息,生成所述目标样品的初始晶型;根据所述目标样品的已知分子结构对初始晶型进行修正,获得修正晶型;根据修正晶型进行晶型预测,获得目标样品的预测晶型。本申请提供的方案,能够降低晶型预测难度,缩短预测时间,提高预测效率。
Description
本申请要求于2021年10月18日提交国家知识产权局、申请号为202111211742.5、申请名称为“晶型预测方法、装置及电子设备”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。
本申请涉及晶型预测技术领域,尤其涉及一种晶型预测方法、装置及电子设备。
同一物质具有两种或两种以上的空间排列和晶胞参数,形成多种晶型的现象称为多晶现象。通过多年的研究发现,同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同,从而影响了药物的稳定性、生物利用度及疗效。因此,通过实验筛选多晶型药物来获取相对稳定的药用晶型已成为标准药物研发过程中一个必不可少的环节。
随着技术的发展,为了减少人为的实验,可以通过计算机辅助发现相对理想的药用晶型。相关技术中,通过模拟对药物分子进行晶型预测(Crystal Structure Prediction,CSP),从而找到潜在的多种稳定晶型,再针对少数明确的潜在晶型进行实验确认,以获得最佳药用晶型。然而,CSP晶型预测受到分子自由度的影响,随着分子复杂度的提高,预测时间和预测难度将急剧提升,从而影响预测效率。
为解决或部分解决相关技术中存在的问题,本申请提供一种晶型预测方法、装置及电子设备,能够降低晶型预测难度,缩短预测时间,提高预测效率。
本申请第一方面提供一种晶型预测方法,其包括:
获取目标样品的多个样品颗粒对应的衍射图像;
根据在各所述衍射图像中获取的参数信息,生成所述目标样品的初始晶型;
根据所述目标样品的已知分子结构对所述初始晶型进行修正,获得修正晶型;
根据所述修正晶型进行晶型预测,获得所述目标样品的预测晶型。
在一实施方式中,所述获取目标样品的多个样品颗粒对应的衍射图像,包括:
通过电子衍射分别获取目标样品的多个样品颗粒在预设温度的拍摄环境中的预设角度范围内的多个衍射图像。
在一实施方式中,所述根据在各所述衍射图像中获取的参数信息,生成所述目标样品的初始晶型,包括:
分别对各所述衍射图像进行指标化处理,获取所述样品颗粒对应的参数信息;其中,所述参数信息包括晶胞参数和衍射点的衍射强度;
将多个所述样品颗粒的参数信息进行合并,获得参数合并信息;其中,所述参数合并信息中的所述衍射点的数量不少于预设数量阈值;
根据所述参数合并信息进行解析,获得所述目标样品的初始晶型;其中,所述初始晶型的分子结构错误率小于或等于预设比例阈值。
在一实施方式中,所述根据所述目标样品的已知分子结构对所述初始晶型进行修正,获得修正晶型,包括:
根据所述目标样品的已知原子和已知基团,删除所述初始晶型中与所述已知原子相异的错误原子以及删除所述初始晶型中与所述已知基团相异的错误基团,获得对应的修正晶型。
在一实施方式中,所述方法还包括:
如果所述初始晶型的分子结构错误率大于所述预设比例阈值,则丢弃所述初始晶型,并重新获取样品颗粒进行电子衍射以生成新的初始晶型。
在一实施方式中,所述方法还包括:如果所述初始晶型的分子结构错误率小于或等于预设比例阈值时,则采纳所述初始晶型。
在一实施方式中,所述根据所述修正晶型进行晶型预测,获得所述目标样品的预测晶型,包括:
将所述修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图;
获取所述沃罗诺伊图中的虚原子信息;
根据所述目标样品的已知分子结构和所述虚原子信息,对所述修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的预测晶型。
在一实施方式中,所述获取所述沃罗诺伊图中的虚原子信息,包括:
获取所述虚原子的中心坐标和半径。
在一实施方式中,所述将所述修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图之后,包括:
根据各所述离散点坐标,获得所述沃罗诺伊图中各区域相交的顶点坐标;
根据各所述顶点坐标和所述离散点坐标,计算获得每一所述顶点坐标与最近的离散点坐标之间的直线距离;
将各所述直线距离分别与预设键长值进行比较,如果所述直线距离小于预设键长值,则删除所述沃罗诺伊图中对应的所述顶点,未删除的顶点对应的顶点坐标作为虚原子的中心坐标。
在一实施方式中,所述根据所述目标样品的已知分子结构和所述虚原子信息,对所述修正晶型中的缺失原子进行预测,包括:
将所述目标样品中的已知分子结构的原子种类和对应的原子中心坐标及将虚原子信息集合中的各虚原子的中心坐标和对应的虚原子半径作为CSP晶型预测的输入结构,对修正晶型中的缺失原子进行预测。
在一实施方式中,所述对所述修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的预测晶型,包括:
根据预测的缺失原子对所述修正晶型的分子结构进行补全,获得至少一个初步预测晶型;
根据所述初步预测晶型的基态能量的数值将各所述初步预测晶型进行能量排序;
选取基态能量最低的初步预测晶型作为所述预测晶型。
在一实施方式中,所述方法还包括:
对所述预测晶型进行验证;其中,当所述预测晶型的模拟结构因子与实验结构因子之间的残差因子小于或等于预设值时,确定所述预测晶型验证通过。
本申请第二方面提供一种晶型预测装置,其包括:
图像获取模块,用于获取目标样品的多个样品颗粒对应的衍射图像;
晶型生成模块,用于根据在各所述衍射图像中获取的参数信息,生成所述目标样品的初始晶型;
晶型修正模块,用于根据所述目标样品的已知分子结构对所述初始晶型进行修正,获得修正晶型;
晶型预测模块,用于根据所述修正晶型进行晶型预测,获得所述目标样品的预测晶型。
在一实施方式中,所述装置还包括:
参数处理模块,用于分别对各所述衍射图像进行指标化处理,获取所述目标样品对应的参数信息;将多个所述目标样品的参数信息进行合并,获得参数合并信息;其中,所述参数合并信息中的衍射点的数量不少于预设数量阈值。
在一实施方式中,所述装置还包括:
晶型验证模块,用于对预测晶型进行验证;其中,当所述预测晶型的模拟结构因子与实验结构因子之间的残差因子小于或等于预设值时,确定所述预测晶型验证通过。
在一实施方式中,所述晶型修正模块用于根据所述目标样品的已知原子和已知基团,删除所述初始晶型中与已知原子相异的错误原子以及删除所述初始晶型中与已知基团相异的错误基团,获得对应的所述修正晶型。
在一实施方式中,所述晶型预测模块还用于将所述修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图;获取所述沃罗诺伊图中的虚原子信息;根据所述目标样品的已知分子结构和虚原子信息,对所述修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的所述预测晶型。
本申请第三方面提供一种电子设备,包括:
处理器;以及
存储器,其上存储有可执行代码,当所述可执行代码被所述处理器执 行时,使所述处理器执行如上所述的方法。
本申请第四方面提供一种计算机可读存储介质,其上存储有可执行代码,当所述可执行代码被电子设备的处理器执行时,使所述处理器执行如上所述的方法。
依据本申请实施例提供的晶型预测方法,先通过获得目标样品的多个样品颗粒的衍射图像,再通过衍射图像获得所需的参数信息以获得初始晶型后,再对初始晶型进行修正以获得修正晶型,最后在修正晶型的基础上进行晶型预测以获得目标样品的预测晶型。这样的设计,相比于直接根据目标样品的已知分子结构进行晶型预测,本申请的预测方式可以预先排除部分错误晶型的干扰,从而针对性地在修正晶型的基础上进行预测,降低了预测难度,缩短了预测时间,提高晶型预测效率。
依据本申请实施例提供的晶型预测装置,先通过图像获取模块获得样品颗粒的衍射图像,再通过参数处理模块根据衍射图像获得所需的参数合并信息,晶型生成模块根据参数合并信获得初始晶型后,晶型修正模块再对初始晶型进行修正以获得修正晶型,最后晶型预测模块在修正晶型的基础上进行晶型预测以获得预测晶型,晶型验证模块验证预测晶型的可信度。这样的设计,相比于直接根据目标样品的已知分子结构进行晶型预测,本申请的预测方式可以预先排除部分错误晶型的干扰,从而针对性地在修正晶型的基础上进行预测,降低了预测难度,缩短了预测时间,提高晶型预测效率;另外,相比于X射线单晶衍射,本申请的装置直接利用电子衍射可以降低对样品质量的要求,降低培养样品的成本,缩短整体的晶型预测时间,提高预测效率。
应当理解的是,以上的一般描述和后文的细节描述仅是示例性和解释性的,并不能限制本申请。
通过结合附图对本申请示例性实施方式进行更详细的描述,本申请的上述以及其它目的、特征和优势将变得更加明显,其中,在本申请示例性 实施方式中,相同的参考标号通常代表相同部件。
图1是本申请实施例示出的晶型预测方法的流程示意图;
图2是本申请实施例示出的晶型预测方法的另一流程示意图;
图3是本申请实施例示出的晶型预测装置的结构示意图;
图4是本申请实施例示出的晶型预测装置的另一结构示意图;
图5是本申请实施例示出的电子设备的结构示意图。
下面将参照附图更详细地描述本申请的实施方式。虽然附图中显示了本申请的实施方式,然而应该理解,可以以各种形式实现本申请而不应被这里阐述的实施方式所限制。相反,提供这些实施方式是为了使本申请更加透彻和完整,并且能够将本申请的范围完整地传达给本领域的技术人员。
在本申请使用的术语是仅仅出于描述特定实施例的目的,而非旨在限制本申请。在本申请和所附权利要求书中所使用的单数形式的“一种”、“所述”和“该”也旨在包括多数形式,除非上下文清楚地表示其他含义。还应当理解,本文中使用的术语“和/或”是指并包含一个或多个相关联的列出项目的任何或所有可能组合。
应当理解,尽管在本申请可能采用术语“第一”、“第二”、“第三”等来描述各种信息,但这些信息不应限于这些术语。这些术语仅用来将同一类型的信息彼此区分开。例如,在不脱离本申请范围的情况下,第一信息也可以被称为第二信息,类似地,第二信息也可以被称为第一信息。由此,限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。在本申请的描述中,“多个”的含义是两个或两个以上,除非另有明确具体的限定。
本申请实施例提供一种晶型预测方法,能够降低预测难度,缩短预测时间,提高预测效率。
以下结合附图详细描述本申请实施例的技术方案。
图1是本申请实施例示出的晶型预测方法的流程示意图。
参见图1,本申请一实施例的晶型预测方法,包括:
步骤S110,获取目标样品的多个样品颗粒对应的衍射图像。
其中,预先将目标样品制成粉末形态,从而获得多个样品颗粒。在一实施方式中,可以通过电子衍射获得每一样品颗粒对应的衍射图像。在一实施方式中,可以获取单个样品颗粒在不同角度进行拍摄获得的对应的衍射图像,从而获得样品颗粒在多角度下的衍射图像,以便后续步骤提取不同角度下的参数信息。
步骤S120,根据各样品颗粒的衍射图像中获取的参数信息,生成目标样品的初始晶型。
其中,参数信息包括晶胞参数和衍射点的衍射强度。根据衍射图像中的衍射花样,可以通过对衍射花样进行标定以获得对应的晶胞参数,例如,晶胞参数可以包括各相交的两个晶面的夹角和相邻两个晶面的晶面间距等。另外,通过根据相关技术测量衍射花样中的各衍射点的衍射强度。
进一步地,通过分别获取各衍射图像中的获取的参数信息并进行汇总合并,从而可以获得数量充分的参数信息,继而可以根据相关技术通过解析参数信息以获得初始晶型。可以理解,晶态物质的组成元素或基团若不相同或其结构有差异,它们的衍射图像在衍射峰数目、角度位置、相对衍射强度次序以至衍射峰的形状上就显现出差异。因此,根据相关技术,对比分析便可以完成目标样品的物相组成和结构的定性鉴定;通过对样品颗粒的各衍射点的衍射强度数据的分析计算,可以完成目标样品的物相组成的定量分析。
步骤S130,根据目标样品的已知分子结构对初始晶型进行修正,获得修正晶型。
可以理解,虽然目标样品的最佳药用晶型未知,但在目标样品的分子结构已知的前提下,根据目标样品的已知分子结构,可以确定该目标样品对应的已知原子和已知基团,从而可以将初始晶型中明显不正确的原子和基团进行删除,从而对初始晶型进行修正,即获得修正后的修正晶型。通过对初始晶型进行初步修正,以便后续步骤在修正晶型的基础上对目标样品进行晶型预测,从而缩小预测范围。
步骤S140,根据修正晶型进行晶型预测,获得目标样品的预测晶型。
其中,根据相关技术中的CSP晶型预测,通过输入修正晶型的结构,即可获得目标样品的预测晶型。
从上述实施例可知,本申请的技术方案,先通过获得目标样品的多个样品颗粒的衍射图像,再通过衍射图像获得所需的参数信息以获得初始晶型后,再对初始晶型进行修正以获得修正晶型,最后在修正晶型的基础上进行晶型预测以获得目标样品的预测晶型。这样的设计,相比于直接根据目标样品的已知分子结构进行晶型预测,本申请的预测方式可以预先排除部分错误晶型的干扰,从而针对性地在修正晶型的基础上进行预测,降低了预测难度,缩短了预测时间,提高晶型预测效率。
图2是本申请实施例示出的晶型预测方法的另一流程示意图。
参见图2,本申请的晶型预测方法,包括:
步骤S210,通过电子衍射分别获取目标样品的多个样品颗粒在预设温度的拍摄环境中的预设角度范围内的多个衍射图像。
本实施例中,通过电子衍射(MicroED)可以获得粉末状的目标样品的多个样品颗粒的衍射图像。进一步地,可以通过电子显微镜,例如透射电镜对样品颗粒进行拍摄以获得衍射图像。在一实施方式中,在拍摄前,预先对样品颗粒及拍摄环境进行冷冻处理,使样品颗粒置于冷冻的拍摄环境中进行电子衍射,以避免在拍摄过程中电子对样品颗粒的破坏,从而确保获得拍摄效果理想的衍射图像。在一实施方式中,预设温度可以是-250℃~0℃。例如-250℃~-50℃、-200℃~-50℃或-200℃~-100℃等。可以理解,
在非冷冻温度下的样品颗粒会被电子破坏,获得的衍射图像的效果不佳。在一实施方式中,可以将若干粉末状的样品颗粒均匀分散在载网上,再将含有样品颗粒的载网通过液氮进行冷冻;接着将冷冻后的载网装入样品杆中,再将样品杆安装于处于冷冻模式的透射电镜,并在冷冻模式下对冷冻的样品颗粒进行拍摄。为了获得不同角度下的样品颗粒的衍射图像,在一实施方式中,将样品杆在预设角度范围内按照预设转速旋转,以获取不同的拍摄视角。例如,将样品杆沿固定轴在-60°~60°的预设角度范围内按照0.5°~1°每秒的转速进行旋转。在一实施方式中,预设角度范围还可以是-45°~45°、-30~30°或-10~10°等。
进一步地,针对样品杆中的至少部分数量的样品颗粒,采用透视电镜在冷冻模式下分别对每一样品颗粒在预设角度范围内获取不同角度下的一系列衍射图像。
需要知道的是,X射线单晶衍射需要大尺寸的质量晶体,然而对于有机分子而言,培养单晶非常困难甚至无法完成,即获得符合的样品的难度非常大。本实施例通过电子衍射作用于粉末状的目标样品,无需耗费大量人力物力培养单晶。
步骤S220,分别获取并合并多个衍射图像中获取的参数信息,获得参数合并信息。
为了获得可供解析的充分数量的参数信息,在一实施方式中,分别对各衍射图像进行指标化处理,获取样品颗粒对应的参数信息;其中,参数信息包括晶胞参数和衍射点的衍射强度;将多个样品颗粒的参数信息进行合并,获得参数合并信息;其中,参数合并信息中的衍射点的数量不少于预设数量阈值。
进一步地,在一实施方式中,针对单个样品颗粒的一系列衍射图像,可以根据相关技术中的指标化软件进行晶体衍射数据的指标化处理,例如DICVOL软件、ipmosflm软件、HKL2000软件、XDS软件等指标化软件。其中,可以在每一张衍射图像中获取对应的参数信息,参数信息包括晶胞参数和衍射点的衍射强度。具体地,参照步骤S120的阐述,于此不再赘述。
进一步地,基于粉末衍射的指标化需要更多的参数信息才能获得尽可能完整的数据,因此,将各样品颗粒的一系列衍射图像进行指标化处理,分别获得对应的每张衍射图像的参数信息后,将各参数进行合并,以获得足够数量的衍射点的衍射强度。其中,当衍射点的数量不少于预设数量阈值时,则表示该参数合并信息符合要求。否则,如果衍射点的数量不足,使得不具有充分的数据进行后续步骤中的解析,则重复步骤S210获得新的样品颗粒的衍射图像或原样品颗粒的新的衍射图像,以使本步骤可以获得充分数量的衍射点。可以理解,预设数量阈值根据不同分子结构的目标样品进行调整,分子结构越复杂的目标样品,需要的衍射点则越多,相应需要的衍射图像越多。
进一步地,在一实施方式中,可以通过相关技术的数据合并软件将各参数信息合并为一套数据,即获得合并参数信息。例如,数据合并软件可以是XSCALE软件。其中,根据数据合并软件,生成的参数合并信息包 括由众多晶胞参数计算出的平均晶胞参数和众多衍射点的衍射强度合并生成的.hkl文件。
步骤S230,根据参数合并信息进行解析,获得初始晶型;其中,初始晶型的分子结构错误率小于或等于预设比例阈值。
可以理解,在获得参数合并信息后,根据参数合并信息,可以根据相关解析软件进行解析,获得初始晶型对应的结构。例如,解析软件可以是SHELXT软件。通过将上述步骤计算出的平均晶胞参数和.hkl文件作为数据源输入解析软件,即可根据该解析软件的相关操作步骤获得初始晶型的结构。
进一步地,在获得初始晶型后,还需根据目标样品的已知分子结构判定初始晶型的分子结构错误率。在一实施方式中,如果初始晶型的分子结构错误率大于预设比例阈值,则表示该初始晶型的结构与目标样品的已知分子结构偏差过大,则丢弃初始晶型,并重新获取样品颗粒进行电子衍射以生成新的初始晶型。可以理解,初始晶型的结构与目标样品的已知分子结构偏差过大时,则该初始晶型很可能为错误晶型。此时,错误晶型不适用于后续步骤的晶型预测,继而丢弃该偏差较大的初始晶型结构,并需要重复本步骤,重新进行解析,获得分子错误率小于或等于预设比例阈值的初始晶型;或者,重新执行步骤S210和/或步骤S220,以获得新的参数合并信息后,再重新对参数合并信息进行解析,以获得符合初始晶型的分子结构错误率小于预设比例阈值初始晶型。在一实施方式中,分子结构错误率可以是初始晶型中的分子结构中的错误原子和错误基团数量之和与总原子和总基团的数量之和的比值;当该比值小于或等于预设比例阈值时,则表示该初始晶型可采纳并用于预测,以助于缩小晶型预测范围。
需要理解的是,根据参数合并信息进行解析,有且获得一个符合条件的初始晶型,只需在一个初始晶型的基础上进行后续步骤,精简了计算量,提高了预测效率。
步骤S240,根据样品颗粒的已知原子和已知基团,删除初始晶型中与已知原子相异的错误原子以及删除初始晶型中与已知基团相异的错误基团,获得对应的修正晶型。
可以理解,在获得初始晶型后,还需要对初始晶型进行精修,以提高 晶型的适配度。进一步地,根据目标样品的已知分子结构中的已知原子和已知基团,可以删除初始晶型中明显不同于已知分子结构的错误原子和错误基团。具体地,可以在解析软件中进行操作删除,只保留与已知分子结构完全匹配的原子和基团,从而获得对应的修正晶型。
步骤S250,根据修正晶型进行晶型预测,获得预测晶型。
在一实施方式中,将修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图;获取沃罗诺伊图中的虚原子信息;根据目标样品的已知分子结构和虚原子信息,对修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的预测晶型。
具体地,可以将修正晶型中的原子作为离散点,原子坐标作为离散点坐标,绘制沃罗诺伊图(Voronoi Diagram),从而对修正晶型的三维空间进行分割。进一步地,在沃罗诺伊图的每块区域中均包含一个离散点(即一个原子),则每块区域的边缘不会再出现另外一个离散点。因此,沃罗诺伊图中的多块区域相交的顶点及顶点周围的不包含离散点的空间即为不会出现原子的空间,这些空间可以作为虚原子产生的空间,沃罗诺伊图中的多块区域相交的部分顶点的坐标可以作为对应的虚原子中心坐标。
其中,单个虚原子信息可以是虚原子的中心坐标和半径,通过获取虚原子信息,以助于预测晶型的分子内坐标的构建。在一实施方式中,通过获取与最近离散点的直线距离大于或等于预设键长值的各顶点对应的坐标,即可获得各虚原子对应的坐标。也就是说,仅有部分符合条件的顶点的坐标可以作为虚原子的中心坐标,该顶点与其最近离散点的直线距离的一半即为对应的虚原子的半径。进一步地,在一实施方式中,根据各离散点坐标,通过相关技术计算获得各区域相交的顶点坐标;根据各顶点坐标和离散点坐标,可以计算获得每一顶点坐标与其最近的离散点坐标之间的直线距离;将各直线距离分别与预设键长值进行比较,如果直线距离小于预设键长值,则删除沃罗诺伊图中对应的顶点。即删除的顶点不用作虚原子,未删除的顶点的坐标作为虚原子的中心坐标。其中,预设键长值可以是常见化学键长的1/2。常见化学键长可以是1~1.5Angstrom。在一实施方式中,预设键长值可以是0.5~0.75Angstrom,如0.5Angstrom、0.6Angstrom、0.7Angstrom或0.75Angstrom。需要理解的是,沃罗诺伊图中的各区域未 删除的相交的顶点作为虚原子,虚原子与最近的离散点,即虚原子与最近的原子之间的直线距离需要和常见化学键长的1/2近似,如果该顶点与最近的原子之间的直线距离太小,则,该顶点不利于正常的分子结构的构建,即该顶点不适合作为虚原子。因此,通过删除沃罗诺伊图中直线距离小于预设键长值的顶点,从而删除不适合的虚原子。
进一步地,在删除不适合的顶点,即删除不适合的虚原子后,在一实施方式中,将剩余顶点作为对应的虚原子的中心坐标,并将各顶点与最近原子距离的一半作为对应的虚原子半径,获得虚原子信息集合。其中,虚原子信息集合中的各虚原子将作为构建预测晶型的障碍物,即存在虚原子的位置将不会存在预测晶型的原子,从而辅助预测晶型的结构的搭建。
进一步地,在一实施方式中,根据目标样品的已知分子结构和虚原子信息,对修正晶型中的缺失原子进行预测,包括:将目标样品中的已知分子结构的原子种类和对应的原子中心坐标及将虚原子信息集合中的各虚原子的中心坐标和对应的虚原子半径作为CSP晶型预测的输入结构,从而对修正晶型中的缺失原子进行预测。通过获得缺失原子,进一步地,在一实施方式中,根据预测的缺失原子对修正晶型的分子结构进行补全,获得至少一个初步预测晶型;根据初步预测晶型的基态能量的数值将各初步预测晶型进行能量排序;选取基态能量最低的初步预测晶型作为预测晶型。可以理解,CSP晶型预测可以根据相关技术进行,于此不作赘述。
可以理解,在对修正晶型进行原子补全后,获得的初步预测晶型可能有多个。根据相关技术进行计算,可以获得每一初步预测晶型的基态能量,再根据基态能量的数值大小将各初步预测晶型按照能量大小进行排序,即可将基态能量值最低的初步预测晶型作为预测晶型。可以理解,基态能量值越低,晶型越稳定,从而可以作为理想的药用晶型。
步骤S260,对预测晶型进行验证,获得验证通过的预测晶型。
可以理解,在获得预测晶型后,为了确保预测晶型的正确性,可以对预测晶型进行验证。
在一实施方式中,对预测晶型进行验证;其中,当预测晶型的模拟结构因子与实验结构因子之间的残差因子小于或等于预设值时,确定预测晶型验证通过。在一实施方式中,预设值可以为0.3~0.4,例如0.3、0.35或 0.4。
在一实施方式中,残差因子R
1根据下述公式(1)计算获得:
其中,R
1代表残差因子,Fcalc代表模拟结构因子,Fobs代表实验结构因子。
进一步地,模拟结构因子Fcalc可根据下述公式(2)计算获得:
其中,i表示虚数单位,j表示晶胞内第j个原子,n表示预测晶型的晶胞内的所有原子总数,x、y、z分别为预测晶型的晶胞中的原子的分数坐标,h、k、l为衍射点对应的密勒指数。
实验结构因子根据上述步骤S220中的各衍射点的衍射强度合并获得,具体可参考下述公式(3)计算获得实验结构因子。
I(hkl)∝|F(hkl)|
2 (3)
其中,hkl为各衍射点对应的密勒指数,I(hkl)为衍射点的衍射强度,F(hkl)为实验结构因子。
可以理解,当预测晶型的残差因子数值小于或等于预设值时,则表示该预测晶型的结构正确,即为验证通过。验证通过的预测晶型即为理想的药用晶型。否则,如果残差因子大于预设值,则表示验证不通过。
如果验证不通过,则将步骤S250中的各初步预测晶型的基态能量排序的数值为次低的初步预测晶型作为预测晶型,进一步重复本步骤进行验证,直至验证通过,获得验证通过的预测晶型。可以理解,验证通过的预测晶型即为正确的且最稳定的晶型。
从该实施例可以看出,本申请的晶型预测方法,通过电子衍射技术获 得粉末状的各样品颗粒的多个不同角度的衍射图像后,通过解析各衍射图像获得充分数量的衍射点的参数合并信息,从而根据参数合并信息获得初始晶型,且只需初始晶型的分子结构错误率小于或等于预设比例阈值即可作为后续预测的基础,有效减少了初始结构的数量,从而降低了后续预测的计算时间。这样的设计,相比于X射线单晶衍射,本申请极大地降低了对样品质量与性质的依赖,减少了培养样品的成本。另外,通过对初始晶型进行修正,获得的修正晶型即可作为CSP晶型预测的输入结构以作为实验参考,有效减少了降低了因样品分子自由度对CSP晶型预测的深度影响,降低了CSP预测难度;另外通过验证预测晶型以提高预测晶型的可信度,从而获得正确且稳定的预测晶型。本实施例的晶型预测方法,不限于样品种类,通过将电子衍射与CSP晶型预测技术结合以获得预测晶型,降低了样品培养难度及降低了CSP的晶型预测难度,且可以获得可信度高的理想晶型,具有推广价值。
与前述应用功能实现方法实施例相对应,本申请还提供了一种晶型预测装置、电子设备及相应的实施例。
图3是本申请实施例示出的晶型预测装置的结构示意图。
参见图3,本申请的晶型预测装置,包括图像获取模块310、晶型生成模块320、晶型修正模块330及晶型预测模块340,其中:
图像获取模块310用于获取目标样品的多个样品颗粒对应的衍射图像。
晶型生成模块320用于根据在各衍射图像中获取的参数信息,生成所述目标样品的初始晶型。
晶型修正模块330用于根据目标样品的已知分子结构对初始晶型进行修正,获得修正晶型。
晶型预测模块340用于根据修正晶型进行晶型预测,获得目标样品的预测晶型。
图4是本申请实施例示出的晶型预测装置的结构示意图。
参见图4,进一步地,在一实施方式中,本申请的图像获取模块310用于通过电子衍射分别获取各样品颗粒在预设温度的拍摄环境中的预设角度范围内的多个衍射图像。
进一步地,在一实施方式中,本申请的装置还包括参数处理模块350, 参数处理模块350用于分别对各衍射图像进行指标化处理,获取样品颗粒对应的参数信息;将多个样品颗粒的参数信息进行合并,获得参数合并信息;其中,参数合并信息中的衍射点的数量不少于预设数量阈值。晶型生成模块320用于根据参数合并信息进行解析,获得初始晶型;其中,初始晶型的分子结构错误率小于或等于预设比例阈值。在一实施方式中,如果晶型生成模块320生成的初始晶型的分子结构错误率大于预设比例阈值,则丢弃初始晶型,并重新获取样品颗粒进行电子衍射以生成新的初始晶型。
进一步地,在一实施方式中,晶型修正模块330用于根据目标样品的已知原子和已知基团,删除初始晶型中与已知原子相异的错误原子以及删除初始晶型中与已知基团相异的错误基团,获得对应的修正晶型。
进一步地,在一实施方式中,晶型预测模块340还用于将修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图;获取沃罗诺伊图中的虚原子信息;根据目标样品的已知分子结构和虚原子信息,对修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的预测晶型。晶型预测模块340还用于根据预测的缺失原子对修正晶型的分子结构进行补全,获得至少一个初步预测晶型;根据初步预测晶型的基态能量的数值将各初步预测晶型进行能量排序;选取基态能量最低的初步预测晶型作为预测晶型。
进一步地,在一实施方式中,本申请的装置还包括晶型验证模块360,晶型验证模块360用于对预测晶型进行验证;其中,当预测晶型的模拟结构因子与实验结构因子之间的残差因子小于或等于预设值时,确定预测晶型验证通过。
从该实施例可以看出,本申请的晶型预测装置,先通过图像获取模块获得样品颗粒的衍射图像,再通过参数处理模块根据衍射图像获得所需的参数合并信息,晶型生成模块根据参数合并信获得初始晶型后,晶型修正模块再对初始晶型进行修正以获得修正晶型,最后晶型预测模块在修正晶型的基础上进行晶型预测以获得预测晶型,晶型验证模块验证预测晶型的可信度。这样的设计,相比于直接根据目标样品的已知分子结构进行晶型预测,本申请的预测方式可以预先排除部分错误晶型的干扰,从而针对性地在修正晶型的基础上进行预测,降低了预测难度,缩短了预测时间,提高晶型预测效率;另外,相比于X射线单晶衍射,本申请的装置直接利用 电子衍射可以降低对样品质量的要求,降低培养样品的成本,缩短整体的晶型预测时间,提高预测效率。
关于上述实施例中的装置,其中各个模块执行操作的具体方式已经在有关该方法的实施例中进行了详细描述,此处将不再做详细阐述说明。
图5是本申请实施例示出的电子设备的结构示意图。
参见图5,电子设备1000包括存储器1010和处理器1020。
处理器1020可以是中央处理单元(Central Processing Unit,CPU),还可以是其他通用处理器、数字信号处理器(Digital Signal Processor,DSP)、专用集成电路(Application Specific Integrated Circuit,ASIC)、现场可编程门阵列(Field-Programmable Gate Array,FPGA)或者其他可编程逻辑器件、分立门或者晶体管逻辑器件、分立硬件组件等。通用处理器可以是微处理器或者该处理器也可以是任何常规的处理器等。
存储器1010可以包括各种类型的存储单元,例如系统内存、只读存储器(ROM)和永久存储装置。其中,ROM可以存储处理器1020或者计算机的其他模块需要的静态数据或者指令。永久存储装置可以是可读写的存储装置。永久存储装置可以是即使计算机断电后也不会失去存储的指令和数据的非易失性存储设备。在一些实施方式中,永久性存储装置采用大容量存储装置(例如磁或光盘、闪存)作为永久存储装置。另外一些实施方式中,永久性存储装置可以是可移除的存储设备(例如软盘、光驱)。系统内存可以是可读写存储设备或者易失性可读写存储设备,例如动态随机访问内存。系统内存可以存储一些或者所有处理器在运行时需要的指令和数据。此外,存储器1010可以包括任意计算机可读存储媒介的组合,包括各种类型的半导体存储芯片(例如DRAM,SRAM,SDRAM,闪存,可编程只读存储器),磁盘和/或光盘也可以采用。在一些实施方式中,存储器1010可以包括可读和/或写的可移除的存储设备,例如激光唱片(CD)、只读数字多功能光盘(例如DVD-ROM,双层DVD-ROM)、只读蓝光光盘、超密度光盘、闪存卡(例如SD卡、min SD卡、Micro-SD卡等)、磁性软盘等。计算机可读存储媒介不包含载波和通过无线或有线传输的瞬间电子信号。
存储器1010上存储有可执行代码,当可执行代码被处理器1020处理 时,可以使处理器1020执行上文述及的方法中的部分或全部。
此外,根据本申请的方法还可以实现为一种计算机程序或计算机程序产品,该计算机程序或计算机程序产品包括用于执行本申请的上述方法中部分或全部步骤的计算机程序代码指令。
或者,本申请还可以实施为一种计算机可读存储介质(或非暂时性机器可读存储介质或机器可读存储介质),其上存储有可执行代码(或计算机程序或计算机指令代码),当可执行代码(或计算机程序或计算机指令代码)被电子设备(或服务器等)的处理器执行时,使处理器执行根据本申请的上述方法的各个步骤的部分或全部。以上已经描述了本申请的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。本文中所用术语的选择,旨在最好地解释各实施例的原理、实际应用或对市场中的技术的改进,或者使本技术领域的其它普通技术人员能理解本文披露的各实施例。
Claims (20)
- 一种晶型预测方法,其特征在于,包括:获取目标样品的多个样品颗粒对应的衍射图像;根据在各所述衍射图像中获取的参数信息,生成所述目标样品的初始晶型;根据所述目标样品的已知分子结构对所述初始晶型进行修正,获得修正晶型;根据所述修正晶型进行晶型预测,获得所述目标样品的预测晶型。
- 根据权利要求1所述的方法,其特征在于,所述获取目标样品的多个样品颗粒对应的衍射图像,包括:通过电子衍射分别获取所述目标样品的多个样品颗粒在预设温度的拍摄环境中的预设角度范围内的多个衍射图像。
- 根据权利要求1所述的方法,其特征在于,所述根据在各所述衍射图像中获取的参数信息,生成所述目标样品的初始晶型,包括:分别对各所述衍射图像进行指标化处理,获取所述样品颗粒对应的参数信息;其中,所述参数信息包括晶胞参数和衍射点的衍射强度;将多个所述样品颗粒的参数信息进行合并,获得参数合并信息;其中,所述参数合并信息中的所述衍射点的数量不少于预设数量阈值;根据所述参数合并信息进行解析,获得所述目标样品的初始晶型;其中,所述初始晶型的分子结构错误率小于或等于预设比例阈值。
- 根据权利要求1所述的方法,其特征在于,所述根据所述目标样品的已知分子结构对所述初始晶型进行修正,获得修正晶型,包括:根据所述目标样品的已知原子和已知基团,删除所述初始晶型中与所述已知原子相异的错误原子以及删除所述初始晶型中与所述已知基团相异的错误基团,获得对应的修正晶型。
- 根据权利要求3所述的方法,其特征在于,所述方法还包括:如果所述初始晶型的分子结构错误率大于所述预设比例阈值,则丢弃所述初始晶型,并重新获取样品颗粒进行电子衍射以生成新的初始晶型。
- 根据权利要求3所述的方法,其特征在于,所述方法还包括:如果所述初始晶型的分子结构错误率小于或等于预设比例阈值时,则 采纳所述初始晶型。
- 根据权利要求1至6中任一项所述的方法,其特征在于,所述根据所述修正晶型进行晶型预测,获得所述目标样品的预测晶型,包括:将所述修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图;获取所述沃罗诺伊图中的虚原子信息;根据所述目标样品的已知分子结构和所述虚原子信息,对所述修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的预测晶型。
- 根据权利要求7所述的方法,其特征在于,所述获取所述沃罗诺伊图中的虚原子信息,包括:获取所述虚原子的中心坐标和半径。
- 根据权利要求7所述的方法,其特征在于,所述将所述修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图之后,包括:根据各所述离散点坐标,获得所述沃罗诺伊图中各区域相交的顶点坐标;根据各所述顶点坐标和所述离散点坐标,计算获得每一所述顶点坐标与最近的离散点坐标之间的直线距离;将各所述直线距离分别与预设键长值进行比较,如果所述直线距离小于预设键长值,则删除所述沃罗诺伊图中对应的所述顶点,未删除的顶点对应的顶点坐标作为虚原子的中心坐标。
- 根据权利要求7所述的方法,其特征在于,所述根据所述目标样品的已知分子结构和所述虚原子信息,对所述修正晶型中的缺失原子进行预测,包括:将所述目标样品中的已知分子结构的原子种类和对应的原子中心坐标及将虚原子信息集合中的各虚原子的中心坐标和对应的虚原子半径作为CSP晶型预测的输入结构,对修正晶型中的缺失原子进行预测。
- 根据权利要求7所述的方法,其特征在于,所述对所述修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的预测晶型,包括:根据预测的缺失原子对所述修正晶型的分子结构进行补全,获得至少一个初步预测晶型;根据所述初步预测晶型的基态能量的数值将各所述初步预测晶型进 行能量排序;选取基态能量最低的初步预测晶型作为所述预测晶型。
- 根据权利要求1至6中任一项所述的方法,其特征在于,所述方法还包括:对所述预测晶型进行验证;其中,当所述预测晶型的模拟结构因子与实验结构因子之间的残差因子小于或等于预设值时,确定所述预测晶型验证通过。
- 根据权利要求12所述的方法,其特征在于,所述方法还包括:当所述预测晶型的模拟结构因子与实验结构因子之间的残差因子大于所述预设值时,依次将各初步预测晶型的基态能量排序的数值为次低的初步预测晶型作为预测晶型进行验证,直至所述预测晶型验证通过。
- 一种晶型预测装置,其特征在于,包括:图像获取模块,用于获取目标样品的多个样品颗粒对应的衍射图像;晶型生成模块,用于根据在各所述衍射图像中获取的参数信息,生成所述目标样品的初始晶型;晶型修正模块,用于根据所述目标样品的已知分子结构对所述初始晶型进行修正,获得修正晶型;晶型预测模块,用于根据所述修正晶型进行晶型预测,获得所述目标样品的预测晶型。
- 根据权利要求14所述的装置,其特征在于,所述装置还包括:参数处理模块,用于分别对各所述衍射图像进行指标化处理,获取所述目标样品对应的参数信息;将多个所述目标样品的参数信息进行合并,获得参数合并信息;其中,所述参数合并信息中的衍射点的数量不少于预设数量阈值。
- 根据权利要求14所述的装置,其特征在于,所述装置还包括:晶型验证模块,用于对预测晶型进行验证;其中,当所述预测晶型的模拟结构因子与实验结构因子之间的残差因子小于或等于预设值时,确定所述预测晶型验证通过。
- 根据权利要求14所述的装置,其特征在于:所述晶型修正模块用于根据所述目标样品的已知原子和已知基团,删 除所述初始晶型中与已知原子相异的错误原子以及删除所述初始晶型中与已知基团相异的错误基团,获得对应的所述修正晶型。
- 根据权利要求14所述的装置,其特征在于:所述晶型预测模块还用于将所述修正晶型中的原子坐标作为离散点坐标,生成沃罗诺伊图;获取所述沃罗诺伊图中的虚原子信息;根据所述目标样品的已知分子结构和虚原子信息,对所述修正晶型中的缺失原子进行预测,获得基态能量符合预设规则的所述预测晶型。
- 一种电子设备,其特征在于,包括:处理器;以及存储器,其上存储有可执行代码,当所述可执行代码被所述处理器执行时,使所述处理器执行如权利要求1-13中任一项所述的方法。
- 一种计算机可读存储介质,其上存储有可执行代码,当所述可执行代码被电子设备的处理器执行时,使所述处理器执行如权利要求1-13中任一项所述的方法。
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