CN113908274B

CN113908274B - Method for promoting dissociation of organic small molecule ligand and dopamine receptor

Info

Publication number: CN113908274B
Application number: CN202111152336.6A
Authority: CN
Inventors: 李阳梅; 向左鲜; 孙岚; 戎有英; 黄崟东; 张子义
Original assignee: National Defense Technology Innovation Institute PLA Academy of Military Science
Current assignee: National Defense Technology Innovation Institute PLA Academy of Military Science
Priority date: 2021-09-29
Filing date: 2021-09-29
Publication date: 2022-10-11
Anticipated expiration: 2041-09-29
Also published as: CN113908274A

Abstract

The invention relates to the technical field of biophysics, in particular to a method for promoting dissociation of an organic small molecular ligand and a dopamine receptor. The method comprises the following steps: irradiating the combination of the small organic molecule ligand and the dopamine receptor by adopting terahertz waves to promote the dissociation of the small organic molecule ligand and the dopamine receptor; the center frequency of the terahertz wave is in the range of 0.1-10 THz, and the electric field intensity is 0.2-2.0V/nm. The invention discovers that when the terahertz wave is adopted to irradiate the combination body of the dopamine receptor and the anti-psychotropic small molecules, the blockage of the amino acid side chain at the port of the dopamine receptor can be removed, and the terahertz wave can also generate resonance with the rotation of the drug small molecules so as to reduce the combination capacity of the drug small molecules and the dopamine receptor and finally promote the dissociation of the drug small molecules and the dopamine receptor. The method is a noninvasive electromagnetic control method, and does not affect other biological tissues, so the method has wide application prospect in future intervention treatment.

Description

Method for promoting dissociation of organic small molecule ligand and dopamine receptor

Technical Field

The invention relates to the technical field of biophysics, in particular to a method for promoting dissociation of an organic small molecular ligand and a dopamine receptor.

Background

Dopamine (Dopamine) is an important neurotransmitter that regulates a wide variety of physiological processes, such as reward, addiction, memory, metabolism, and hormone secretion. It has been shown that the action of dopamine is mediated by five dopamine receptor proteins (i.e. dopamine D1, D2, D3, D4, D5 receptors) and that disturbances of their functional systems are associated with schizophrenia, parkinson's disease and depression. Antipsychotics or nerve blockers are a group of drugs used in the treatment of schizophrenia and other psychotic disorders. Its main therapeutic action is related to its dopamine-resisting action, and the clinical practice shows that the therapeutic dose of antipsychotic drug is linearly related to its dopamine-receptor blocking action. There are many dopamine receptors in the central nervous system, and most of the currently marketed antipsychotics use dopamine D2 receptors as the primary target, blocking their pathways.

Antipsychotics, although one of the most widely used drugs in patients with schizophrenia and autism, are often associated with serious side effects. The most important side effect, extrapyramidal symptoms (EPS), is manifested by abnormal muscle tone, parkinson-like disease, stiff limbs or inability to sit quietly, and delayed dyskinesia may be caused by long-term administration. Studies have shown that antipsychotics are closely related to the dissociation time and the magnitude of side effects produced by dopamine D2 receptors, with longer dissociation times or slower dissociation rates producing stronger side effects on the limb. Ideally, it would be desirable for an anti-psychotic drug to effectively occupy dopamine receptors and block their function, then rapidly dissociate and allow normal dopamine neurotransmission. Although the new generation of low side effect drugs are continuously designed, the design of new drug molecules is a long-term process consuming a lot of manpower and material resources, and reasonable drug molecules can be designed by designing targets aiming at the potential drugs of the receptors disclosed in the basic research and referring to the chemical structure characteristics of other generic ligands or natural products according to the research results of life sciences such as biochemistry, molecular biology, genetics and the like. This process generally requires an average of 7000 to ten thousand compounds to obtain a new drug, which takes more than 10 years from development to marketing, and thus the development efficiency is particularly low. If the side effects of the anti-mental drugs can be reduced on the basis of the existing anti-mental drugs with better curative effects, the development cost can be greatly saved, and the acceptance and the matching degree of patients to the drugs can be improved, thereby improving the cure rate.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a method for promoting the dissociation of an organic small molecule ligand and a dopamine receptor.

In a first aspect, the present invention provides a method of promoting dissociation of an organic small molecule ligand and a dopamine receptor, comprising: irradiating the combination of the small organic molecule ligand and the dopamine receptor by adopting terahertz waves to promote the dissociation of the small organic molecule ligand and the dopamine receptor;

the center frequency of the terahertz wave is in the range of 0.1-10 THz, and the electric field intensity is 0.2-2.0V/nm.

The invention discloses a terahertz wave which is a high-frequency electromagnetic field with the frequency range of 0.1-10 THz, and the invention discovers that when the terahertz wave is adopted to irradiate a combination body of a dopamine D2 receptor and an antipsychotic drug risperidone, the terahertz wave influences the combination of the dopamine D2 receptor and the risperidone from two aspects, on one hand, a Tryptophan (TRP) side chain on a first outer ring of the dopamine D2 receptor forms a hydrophobic sheet, the hydrophobic sheet is positioned at a port of the dopamine D2 receptor and points to a core of the receptor, and the ingress and egress of risperidone molecules combined with the receptor is controlled like a top hat or a fan. When terahertz waves are irradiated, the terahertz waves and tryptophan side chains resonate to cause the dihedral angle of N-CA-CB-CG of tryptophan to change, and the side chain hydrophobic sheet of the tryptophan is changed from the original closed state to the open state, which is equivalent to removing the obstacle met by risperidone at the port of the receptor; on the other hand, the terahertz wave resonates with risperidone, so that the dihedral angle of C1-C2-C3-C4 related to the piperidine ring of risperidone changes, the piperidine ring of risperidone rotates, the distance between the protonated nitrogen atom on the piperidine ring and negatively charged Aspartic Acid (ASP) of the dopamine D2 receptor increases, the strength of a salt bridge formed between the two increases, and the binding capacity of risperidone and the dopamine D2 receptor decreases. Based on the promotion effects of the two aspects, the risperidone is finally easier to dissociate from a dopamine receptor binding pocket, the binding retention time of the risperidone on a dopamine D2 receptor is greatly reduced, and the side effect of the risperidone on the medicine of the body is reduced.

Furthermore, the center frequency of the terahertz wave is in the range of 3-6 THz, and the electric field intensity is 0.3-0.8V/nm.

Furthermore, the center frequency of the terahertz wave is in the range of 4-5 THz, and the electric field intensity is 0.4-0.6V/nm.

Within the range, the terahertz wave has good efficiency of promoting the dissociation of the organic small molecule ligand and the dopamine receptor.

Further, the electric field polarization direction of the terahertz waves is parallel to the main axis direction of the dopamine receptor protein.

Further, the drug small molecule is a drug small molecule which carries a piperazine ring or a piperidine ring structure and in which a nitrogen atom on the ring is protonated.

The structure can form a salt bridge with a dopamine receptor, the resonance frequency is similar, and the salt bridge is influenced by the reduction of the strength of the salt bridge under the irradiation of terahertz waves, so that the affinity between small drug molecules and the dopamine receptor is reduced.

Further, the dopamine receptor protein is one or more of dopamine D1 receptor protein, dopamine D2 receptor protein, dopamine D3 receptor protein, dopamine D4 receptor protein or dopamine D5 receptor protein. The small drug molecules or other ligand molecules and any dopamine receptor subtype act through a salt bridge, and the binding capacity of the small molecules and dopamine receptors can be reduced only by reducing the strength of the salt bridge, so that dissociation of the small molecules and dopamine receptors is promoted.

It should be noted that if the irradiation of the terahertz wave does not cause the tryptophan hydrophobic sheet at the dopamine D2 receptor port to be removed, as long as the strength of the salt bridge between the small molecule and the dopamine D2 receptor is reduced, the terahertz hydrophobic sheet still has a good effect of promoting the dissociation of the organic small molecule ligand and the dopamine receptor.

Further, the drug small molecule is a dopamine receptor agonist and/or a dopamine receptor antagonist.

Further, the drug small molecule comprises one or more of risperidone, aripiprazole, ziprasidone, haloperidol, spiperone or L-741626.

Further, the promotion of dissociation of the small organic molecule ligand and the dopamine receptor is as follows:

removing the hydrophobic patch barrier at the dopamine receptor port; and/or, reducing the binding capacity of the small organic molecule ligand to the dopamine receptor.

It is further stated that the methods of the present invention for promoting dissociation of small organic molecule ligands and dopamine receptors may be applied to a variety of combinations of dopamine receptors and organic molecules and are not used for any diagnostic or therapeutic purpose. It will be appreciated by those skilled in the art that the method is applicable to a wide variety of non-therapeutic research settings and may play a significant role.

In a second aspect, the present invention provides a method of reducing the side effects of an antipsychotic agent, comprising:

the method is used for promoting separation of dopamine receptor and anti-psychotropic drug.

The dissociation time of the antipsychotic drug from dopamine receptors is closely related to the magnitude of the side effects, with longer dissociation times or slower dissociation rates resulting in stronger side effects on the limb. Therefore, based on the method for promoting the dissociation of the organic small molecule ligand and the dopamine receptor, the method can be applied to promote the separation of the dopamine receptor and the anti-psychotropic drugs, and further has the effect of reducing the side effects of the anti-psychotropic drugs.

In a third aspect, the invention provides a device for promoting dissociation of an organic small molecule ligand and a dopamine receptor, which comprises a terahertz wave emitting device;

the terahertz wave emitting assembly is used for emitting terahertz waves to irradiate the combination body of the small organic molecule ligand and the dopamine receptor so as to promote the dissociation of the small organic molecule ligand and the dopamine receptor;

Further, the polarization direction of the terahertz wave is parallel to the main axis direction of the dopamine receptor.

Further, the organic small molecule ligand is a drug small molecule which carries a piperazine ring or a piperidine ring structure, and nitrogen atoms on the ring are protonated.

removing the hydrophobic patch barrier at the dopamine receptor port;

or reducing the binding capacity of the small organic molecule ligand and dopamine receptor.

The invention further provides the use of the device for promoting dissociation of small organic molecule ligands and dopamine receptors; the use does not include a range of applications for therapeutic purposes.

The invention has the following beneficial effects:

the invention provides a method for promoting dissociation of an organic micromolecule ligand and a dopamine receptor.

Based on the principle, the invention discovers that the method can be applied to reducing the side effect of the anti-mental drugs, only one terahertz wave is required to be introduced into an organism, the terahertz wave can simultaneously and effectively regulate the interaction between the dopamine D2 receptor and the anti-mental drug molecules, and the hydrophobic sheet barrier formed by the tryptophan molecules at the port of the dopamine D2 receptor is removed while the binding capacity between the dopamine D2 receptor and the anti-mental drug molecules is reduced, so that the dissociation of the anti-mental drugs from the receptor is accelerated, and the side effect of the anti-mental drugs on the human body is reduced. The method is regulated and controlled by external terahertz wave irradiation, and the simple, feasible, noninvasive and reversible regulation and control has wide application prospect in future interventional therapy.

Drawings

Fig. 1 is a schematic diagram illustrating that terahertz wave irradiation promotes dissociation of risperidone and dopamine D2 receptors provided in embodiment 1 of the present invention.

Fig. 2 is an atomic structure diagram of tryptophan, aspartic acid and risperidone on a dopamine D2 receptor provided in embodiment 1 of the present invention.

Fig. 3 is a schematic structural diagram of closing and opening of a tryptophan hydrophobic plate before and after terahertz wave irradiation provided in embodiment 1 of the present invention.

Fig. 4 is a schematic diagram of a change in the structure of risperidone molecule and a change in the relative aspartic acid distance before and after terahertz wave irradiation provided in embodiment 1 of the present invention.

FIG. 5 is a schematic diagram of a dihedral angle change of tryptophan N-CA-CB-CG before and after irradiation with terahertz waves, provided by embodiment 1 of the present invention.

Fig. 6 is a schematic diagram of changes in dihedral angles of risperidone molecules C1-C2-C3-C4 before and after terahertz wave irradiation provided in embodiment 1 of the present invention.

Fig. 7 is a schematic diagram illustrating a change in distance between a salt bridge between risperidone molecules and a dopamine D2 receptor before and after terahertz wave irradiation provided in embodiment 1 of the present invention.

Detailed Description

The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.

Example 1

The embodiment provides a dynamic evolution process of a compound of a dopamine D2 receptor and a common antipsychotic drug risperidone under the irradiation of terahertz waves or not, wherein the process is simulated by common molecular dynamics software GROMACS, and the specific modeling and simulation method comprises the following steps:

1. establishment of a mimetic System comprising Risperidone-dopamine D2 receptor Complex

Dopamine D2 receptor (crystal structure from RCSB protein library, ID: 6CM 4) was embedded in a phospholipid bilayer membrane composed of 128 phospholipid molecules using Charmm-GUI, and then placed in 0.15mol/L NaCl solution as a whole. Then, the protonated risperidone molecules (the structures of which are from a ZINC database) are docked to the binding pocket region of the dopamine D2 receptor by using molecular docking software autodock4, so that an initial system for molecular dynamics simulation is established. It should be noted that the risperidone molecules mentioned in this example are all risperidone molecules in which the nitrogen atom on the piperidine ring is protonated, which is the form in which it exists in aqueous solution.

2. Construction of molecular force fields of parts of the system required in the simulation

The preferred amber14sb force field is used to describe all atomic charges, chemical bonds and non-bond interactions in dopamine D2 receptor, phospholipid molecules and saline solution, the copy pe script is used to call the Antechamber module of Ambertools software to generate a topology file of risperidone based on the GAFF force field, the atomic charges of risperidone are obtained by using a restrictive ElectroStatic Potential (RESP) fitting method, and the RESP charges are the atomic charges which are most suitable for flexible small molecules to perform molecular dynamics simulation (including dynamics, molecular docking and the like).

3. Temperature and pressure balance of the system

Before starting the kinetic simulation, the initially constructed system is first subjected to energy minimization, so that the structure of the system is normal, the distance between atoms is not too close, and the aspects of geometric configuration, solvent molecular orientation and the like are reasonable. Then, the system is subjected to temperature equilibrium, so that the average temperature of the system reaches the set simulated temperature 303.15K. And then, carrying out pressure balance on the system to enable the average pressure to reach the set simulated pressure of 1bar. It should be noted that, certain position constraints are imposed on the phospholipid membrane and the dopamine D2 receptor protein during the former temperature and pressure balancing processes, so as to prevent the system from collapsing due to large changes of the positions of the atoms during the balancing processes. Finally, after pressure balance, the position limitation of all atoms is removed, and temperature and pressure balance simulation is continuously carried out for 200ns, so that the temperature and the pressure of the system reach a completely balanced state and are close to a real membrane protein system, and the dynamic simulation process is more accurate.

4. Molecular dynamics simulation under irradiation with/without terahertz wave

After the simulation system was completely balanced, two sets of molecular dynamics simulations were performed, respectively. One group was a control group without terahertz wave irradiation. The other group is an effect group, terahertz wave irradiation is introduced in simulation, the electric field polarization direction of the terahertz wave is consistent with the main shaft of the dopamine D2 receptor, the central frequency of the terahertz wave is 4THz, the electric field intensity is 0.5V/nm, and parameters can be modified through a simulated input file. The two groups of simulation time lengths are both 100ns, and atom track data is recorded every 100ps and is used for subsequent data analysis.

5. The binding free energy between dopamine D2 receptor and risperidone was calculated in the control and effector groups.

The free energy of binding of dopamine D2 receptor to risperidone was calculated using g _ mmpbsa based on the atom trajectory data file, which includes the contributions of four components: van der waals interaction energy, electrostatic interaction energy, polar solvation energy, non-polar solvation energy. It should be noted that the effect of entropy is not considered here.

Fig. 1 shows a schematic diagram of the terahertz wave irradiation provided in this embodiment for promoting dissociation of risperidone and dopamine D2 receptors. As shown in the left panel of fig. 1, in the absence of external terahertz wave irradiation, risperidone (gray-white sphere cluster structure in fig. 1) binds to the dopamine D2 receptor (black helix structure in fig. 1), which is composed of about 409 amino acids linked, wherein the region composed of amino acids near risperidone is called a binding pocket. As shown in the right panel of fig. 1, risperidone dissociates from the dopamine D2 receptor binding pocket in the presence of additional terahertz wave irradiation.

The dopamine D2 receptor has two key amino acids closely related to the binding/dissociation of risperidone molecules, one is tryptophan (abbreviated as TRP, grey white rod structure in figure 1) located at the dopamine D2 receptor port in figure 1, and the side chain is a hydrophobic sheet group pointing to the center of the dopamine D2 receptor, and like a phylum, the side chain can prevent the separation of risperidone from the dopamine D2 receptor; another key amino acid is aspartic acid (abbreviated ASP, gray-white rod-like structure in fig. 1), located in the central binding pocket of the dopamine D2 receptor in fig. 1, which deprotonates in aqueous solution, is negatively charged, and can form a strong salt bridge with the positively charged risperidone in aqueous solution. Salt bridges are a strong electrostatic attraction and their formation allows the dopamine D2 receptor to bind stably to risperidone. Comparing the left and right images in fig. 1, it can be seen that under the terahertz wave irradiation, the hydrophobic side chain of tryptophan deflects and turns to the side of the receptor.

In the embodiment, a compound of a dopamine D2 receptor and risperidone is irradiated by terahertz waves, which can affect the combination of the receptor and the risperidone from two aspects, on one hand, the dopamine D2 receptor has a tryptophan at a first outer ring position, and a side chain of the tryptophan forms a hydrophobic sheet to control the entry and exit of drug molecules like a gate, when the terahertz waves are irradiated, the conformation of the tryptophan is changed, and the hydrophobic sheet is changed from an original closed state to an open state (the specific reason is that the dihedral angle of N-CA-CB-CG of the tryptophan is changed and is introduced later), which is equivalent to that the terahertz waves remove the obstacle of the risperidone at the port of the dopamine D2 receptor; on the other hand, the terahertz wave resonates with the vibration of the risperidone molecule, so that the piperidine ring of the risperidone rotates (specifically, the reason is that the associated dihedral angle of C1-C2-C3-C4 changes, which will be described later), and further, the distance between the protonated nitrogen atom on the piperidine ring and the negatively charged aspartic acid of the dopamine D2 receptor increases, the strength of the salt bridge formed between the protonated nitrogen atom and the negatively charged aspartic acid is reduced, and thus the affinity between the risperidone and the dopamine D2 receptor is reduced. The two aspects of synergistic action finally enable the risperidone to be more easily dissociated from the dopamine D2 receptor binding pocket, and the binding retention time of the risperidone on the dopamine D2 receptor is greatly reduced.

Based on the principle that terahertz waves can reduce the binding capacity between risperidone and dopamine D2 receptors, terahertz wave irradiation can be presumed to promote risperidone to be rapidly dissociated from the dopamine D2 receptors, so that the side effects of the risperidone on the drugs of the organisms are reduced.

Fig. 2 shows an atomic structure diagram of tryptophan, aspartic acid and risperidone on the dopamine D2 receptor provided in this embodiment. In the club structure shown in fig. 2, the different atom types are represented by different sized balls, and the atom positions depicting two important dihedral angles are indicated in fig. 2, which are N, CA, CB, and CG atoms of tryptophan, and C1, C2, C3, and C4 atoms of risperidone, except for N, which is a nitrogen atom, and the remaining 7 atoms are carbon atoms, where the numbering of the atoms in the amino acids is according to the international general rule and the numbering of the atoms in risperidone is free. The key atoms constituting the salt bridge, namely the side chain atom on aspartic acid bearing a negative charge, are also indicated in FIG. 2: CG, OD1, OD2 atoms, and an amino group atom bearing a positive charge on risperidone: n and H atoms, wherein CG, OD1, OD2, N and H sequentially represent carbon, oxygen, nitrogen and hydrogen atoms.

Fig. 3 shows a schematic structural diagram of the closing and opening of the tryptophan hydrophobic plate before and after terahertz wave irradiation provided by the present embodiment. In FIG. 3, the white and black rod-shaped structures represent the structures of tryptophan before and after being irradiated by terahertz waves. Wherein the indolyl group (i.e., pentagon and hexagon structures) on the tryptophan side chain forms a hydrophobic sheet, which is located at the dopamine D2 receptor port, and blocks dissociation of the risperidone molecule from the receptor binding pocket. Under the irradiation of terahertz waves, dihedral angles formed by N, CA, CB and CG atoms in the image change, and an indolyl deflects to the left, which is similar to enlarging the space at a dopamine D2 receptor port.

Fig. 4 shows a schematic diagram of the structural change of risperidone molecule and the change of relative aspartic acid distance before and after terahertz wave irradiation provided by this embodiment. In fig. 4, white rod-shaped structures represent aspartic acid and risperidone before terahertz wave irradiation, and black rod-shaped structures represent structures of both after terahertz wave irradiation. It can be seen that after terahertz wave irradiation, the piperidine ring in the middle of risperidone rotates, the plane of the piperidine ring is changed from the original direction which is deviated to the direction vertical to the paper surface to the subsequent direction which is deviated to the direction parallel to the paper surface, the protonated nitrogen atom on the piperidine ring is far away from the negatively charged side chain group of aspartic acid on the dopamine D2 receptor after rotation, and the strength of the salt bridge formed between the two is presumed to be reduced along with the increase of the distance between the two. The structure of risperidone before being irradiated by terahertz wave is called as a first conformation, and the structure after irradiation is called as a second conformation.

FIG. 5 shows a schematic diagram of the dihedral angle change of tryptophan N-CA-CB-CG before and after irradiation with terahertz waves provided by the embodiment. No terahertz wave is irradiated within the initial 100 nanoseconds, the angle (gray curve) of the dihedral angle of the tryptophan N-CA-CB-CG is about minus 65 degrees, and the introduction of the terahertz wave is started after 100 nanoseconds, so that the angle (black curve) of the dihedral angle of the tryptophan N-CA-CB-CG is instantly changed to about minus 172 degrees. It can be seen that after irradiation by terahertz wave, the change of the dihedral angle of tryptophan is about minus 107 degrees, and the change corresponds to the turning off and turning on of the hydrophobic gate of tryptophan before and after the change.

FIG. 6 shows a schematic diagram of the change of dihedral angles of risperidone molecules C1-C2-C3-C4 before and after terahertz wave irradiation provided by this example. The initial 100 nanoseconds are free from terahertz wave irradiation, the dihedral angle of risperidone molecules C1-C2-C3-C4 is about minus 154 degrees in most of the time, corresponding to the first conformation of the molecular structure, and the dihedral angle of C1-C2-C3-C4 is changed to about minus 66 degrees in a shorter time range from 98 to 100 nanoseconds, corresponding to the second conformation of the risperidone molecular structure. It can be seen that in the absence of terahertz wave irradiation, the risperidone molecular structure is able to transition with a lower probability (about 2%) from a first conformation that stably binds to the receptor to a second conformation that is distant from the binding site. Starting from 100ns later, the introduction of terahertz waves was initiated, and it was found that the C1-C2-C3-C4 dihedral angle remained around negative 154 degrees (corresponding to the first conformation) for the first 5 ns, then the angle changed to around negative 66 degrees (corresponding to the second conformation) and lasted for about 74 ns, the dihedral angle changed by about 88 degrees, which corresponds to the rotation of the piperidine ring in the middle of the risperidone, and finally the C1-C2-C3-C4 dihedral angle changed back to around negative 154 degrees (corresponding to the first conformation). It can be seen that under terahertz wave irradiation, the probability that risperidone assumes the second conformation (i.e., a structure that weakly binds to the receptor) increases from 2% to 74%.

Fig. 7 shows a schematic diagram of the change in the distance between risperidone molecules and aspartate on the dopamine D2 receptor before and after terahertz wave irradiation provided in this embodiment. As can be seen by comparison with fig. 6, the change in salt bridge distance corresponds exactly to the shift in the conformation of the risperidone molecule, and rotation of the piperidine ring of the risperidone molecule corresponds to an increase in the salt bridge distance. No terahertz wave is irradiated within the initial 100 nanoseconds, and the distance between salt bridges formed between aspartic acid and risperidone is only 2.7 nanometers in most of the time, which indicates that the bonding strength between the aspartic acid and the risperidone is strong, and the distance between the salt bridges is increased to about 4.6 nanometers in only 2 nanoseconds. The terahertz wave is introduced from 100 nanoseconds later, the salt bridge distance is increased to 4.6 nanometers in the middle 74 nanoseconds, the salt bridge is strictly broken, and accordingly, the constraint of the risperidone on the dopamine D2 receptor is reduced, and the risperidone is easier to dissociate.

TABLE 1 free energy of binding and energy breakdown between dopamine D2 receptor and risperidone molecule

Further, this example calculates the binding free energy between the dopamine D2 receptor and risperidone molecule in the control group and the effector group and performs energy decomposition, and the results are shown in table 1. It should be noted that only the binding free energy in the period of time (called effective acting time) corresponding to the increase of the salt bridge distance is counted in the results of the effect group. Table 1 shows that under the condition of no terahertz wave irradiation, the free energy of the combination between the dopamine D2 receptor and risperidone is-97.0 kJ/mol, and the negative value shows that the affinity of the dopamine D2 receptor and the risperidone is strong. The binding free energy is the sum of the van der waals interaction energy, the electrostatic interaction energy, the polar solvation energy and the non-polar solvation energy, and as can be seen from the positive and negative values of the values, the van der waals, electrostatic and non-polar solvation interactions (corresponding to negative energy) promote the binding between the dopamine D2 receptor and risperidone, while the polar solvation (corresponding to positive energy) weakens the binding between the two, which corresponds to the energy consumed by the complex to desolvate and align to the binding interface. When 4THz,0.5V/nm terahertz wave irradiation is introduced, the binding free energy between the dopamine D2 receptor and risperidone is changed greatly, the absolute value of the new binding free energy is less than 30% of the absolute value of a control group, and the affinity between the dopamine D2 receptor and the risperidone is reduced greatly. Further, it can be seen that the main changes under the terahertz wave irradiation are the electrostatic interaction energy (127.8 kJ/mol) and the polar solvation energy (-47.5 kJ/mol), which are both related to the change of the salt bridge interaction, and thus are consistent with the previously analyzed change of the salt bridge distance under the terahertz wave irradiation. In summary, the increase of the binding free energy (value) between the dopamine D2 receptor and risperidone under terahertz wave irradiation reflects the decrease of the affinity between the two, so that risperidone molecules are more easily dissociated from the dopamine D2 receptor.

The molecular dynamics simulation can describe the dynamics evolution process of molecules in detail, but under the influence of a calculation algorithm, precision, software and hardware environment, initial random disturbance and the like, a simulation system has a certain chaotic effect, so that completely consistent atom tracks are difficult to obtain in two calculations, but the situation is consistent with the actual observed biological process. For a simulation in an equilibrium state, the nature of the system is deterministic over a long period of time, and multiple simulation results are equivalent because the simulation results can traverse the phase space sufficiently. In this example, in addition to the simulation duration of up to 100ns, repetitive simulations were performed 5 times for the control group and the effect group of the simulation system, respectively, and atom trajectory data was recorded. The respective clustering analysis of the conformation of the risperidone molecule during each simulation proved that the risperidone molecule was mainly switched between the aforementioned first and second conformations, and the probability that the risperidone molecule assumed the second conformation within 100ns of the simulation time is shown in tables 2 and 3, which at the same time represents the probability of salt bridge destruction between risperidone and dopamine D2 receptor, i.e. the probability of dissociation of both.

TABLE 2 probability of occurrence of a second conformation of risperidone without terahertz wave irradiation

Table 2 shows that in the absence of terahertz wave irradiation, risperidone is mostly in a conformation that stably binds to dopamine D2 protein (first conformation), and assumes a second conformation (i.e., away from the binding site) with little probability. The probability of the second conformation in the control group was 2%, which is consistent with the above-mentioned change in dihedral angles of C1-C2-C3-C4 occurring at 2 nanoseconds in a time of 100 nanoseconds, and it is the change in dihedral angles that causes the risperidone to change from the first conformation to the second conformation. The average probability obtained by the control group and 5 times of repeated calculation is 7.8%, and it can be seen that risperidone dissociates from the dopamine D2 receptor with a probability of about 7.8% and stably binds to the receptor with a probability of 92.2% without terahertz wave irradiation.

TABLE 3 probability of risperidone appearing in the second conformation under terahertz wave irradiation

Table 3 shows that, under terahertz wave irradiation, the probability that risperidone exhibits the second conformation is greatly increased, the highest probability is 82.2%, and the average probability obtained by effect group and 5-time repeatability calculation is 66.2%.

The risperidone molecule provided in this example is only one commonly used antipsychotic drug, and other drug molecules such as the piperidine ring on the molecule such as spiperone (spiperone), L-741626, haloperidol (haloperidol) and the piperazine ring on the molecule such as aripiprazole (aripiprazole), ziprasidone (nemonapride) are bound to the dopamine D2 receptor through a salt bridge. In addition, the rotational resonance frequency of the piperazine ring is similar to the resonance frequency of the risperidone piperidine ring, so it is presumed that the above drug molecules are also modulated by the approximate frequency of the terahertz wave, and the specific working principle and technical effect are similar.

Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, it is intended that all such modifications and alterations be included within the scope of this invention as defined in the appended claims.

Claims

1. The application of a device for emitting terahertz waves in preparation of products for promoting dissociation of organic small molecule ligands and dopamine receptors is characterized by comprising the following steps: irradiating the combination of the small organic molecule ligand and the dopamine receptor by using terahertz waves to promote the dissociation of the small organic molecule ligand and the dopamine receptor;

the central frequency of the terahertz wave is in the range of 0.1-10 THz, and the electric field intensity is 0.2-2.0V/nm;

the organic micromolecule ligand is a drug micromolecule which carries a piperazine ring or a piperidine ring structure and nitrogen atoms on the ring are protonated;

the drug micromolecules are dopamine receptor agonists or dopamine receptor antagonists.

2. The use according to claim 1, wherein the terahertz wave has a central frequency in the range of 4 to 5THz and an electric field strength of 0.4 to 0.6V/nm.

3. The use according to claim 1, wherein the terahertz waves have an electric field polarization direction parallel to the direction of the major axis of the dopamine receptor protein.

4. The use according to any one of claims 1 to 3, wherein the dopamine receptor is one or more of a dopamine D1 receptor protein, a dopamine D2 receptor protein, a dopamine D3 receptor protein, a dopamine D4 receptor protein or a dopamine D5 receptor protein.

5. The use of claim 1, wherein the pharmaceutical small molecule comprises one or more of risperidone, aripiprazole, ziprasidone tablet, haloperidol, spiperone, or L-741626.

6. The use according to any one of claims 1 to 3, wherein the promotion of dissociation of the small organic molecule ligand and the dopamine receptor is:

removing the hydrophobic patch blockage at the dopamine receptor port; and/or, reducing the binding capacity of the small organic molecule ligand to the dopamine receptor.