WO2022094870A1 - Relative free energy calculation method which is physically rigorous and which maximizes phase space overlap - Google Patents

Relative free energy calculation method which is physically rigorous and which maximizes phase space overlap Download PDF

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WO2022094870A1
WO2022094870A1 PCT/CN2020/126777 CN2020126777W WO2022094870A1 WO 2022094870 A1 WO2022094870 A1 WO 2022094870A1 CN 2020126777 W CN2020126777 W CN 2020126777W WO 2022094870 A1 WO2022094870 A1 WO 2022094870A1
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free energy
atoms
dihedral
angles
phase space
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邹俊杰
马健
温书豪
赖力鹏
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深圳晶泰科技有限公司
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  • the invention belongs to the technical field of drug design, and in particular relates to a relative free energy calculation method with strict physics and maximum phase space overlap, which is an algorithm supplement for the relative free energy perturbation calculation, so that the relative free energy perturbation calculation can guarantee the physical Strict, and on this premise, the overlap of the phase space can be guaranteed to be maximized.
  • free energy perturbation calculation is a physics-based high-precision method for evaluating the binding strength of small drug molecules and targets. It can effectively remove false positive molecules and improve the design success rate. Accelerate the process of new drug development.
  • the FEP process established based on enhanced sampling algorithm, high-precision molecular force field (Xforce) and rigorous data statistical analysis method needs to accurately calculate the binding free energy of hundreds of small molecule drug candidate compounds and targets in a short time. .
  • the mean unsigned error (mean unsigned error) of XFEP in the calculation of functional group substitution and backbone transition in dozens of test systems and a series of real projects is less than 1.0kcal/mol, and the predicted value and the data obtained in the experiment show significant correlation .
  • free energy perturbation calculation is a physics-based high-precision method for evaluating the binding strength of small drug molecules and targets. It can effectively remove false positive molecules and improve the design success rate. Accelerate the process of new drug development.
  • the FEP process established based on enhanced sampling algorithm, high-precision molecular force field (Xforce) and rigorous data statistical analysis method needs to accurately calculate the binding free energy of hundreds of small molecule drug candidate compounds and targets in a short time. .
  • the mean unsigned error (mean unsigned error) of XFEP in the calculation of functional group substitution and backbone transition in dozens of test systems and a series of real projects is less than 1.0kcal/mol, and the predicted value and the data obtained in the experiment show significant correlation .
  • the purpose of the present invention is to provide a method for calculating relative free energy that is physically strict and maximizes phase space overlap.
  • the present invention provides the following technical solutions:
  • a method for calculating relative free energy that is physically rigorous and maximizes phase space overlap including the following steps:
  • Step A carry out the npt ensemble dynamics simulation process with two molecules to be calculated relative free energy, namely molecule X and molecule Y, to obtain the structure of the equilibrium state;
  • Step B determine the atoms corresponding to each other and to be retained in the two molecules of X and Y, and the atoms that X will disappear and Y will grow; according to the rules, determine the respective angles and two sides of X and Y that need to be removed to achieve physical strictness angle, and the respective additional dihedral angles added to X and Y to maximize phase space overlap;
  • Step C In the calculation of the relative free energy of the change from X to Y, increase the lambda value to remove the excess angle and dihedral angle between the atoms to be disappeared and the remaining atoms on X; decrease the lambda value and remove the effect of the The superfluous angle and dihedral effect between the atoms to be disappeared and the remaining atoms;
  • Step D In the calculation of relative free energy, the free energy required to remove excess and dihedral angles and add additional dihedral angles is statistically calculated, and this part of the free energy is included in the total free energy of the change from X to Y.
  • step C the equilibrium value of the fixed dihedral angle is taken from the respective balanced structures of X and Y in step A.
  • Fig. 1 is the bond topology diagram of the molecule of Example 1;
  • Fig. 2 is the bond topology diagram of the molecule of Example 2;
  • FIG. 3 is a bond topology diagram of the molecule of Example 31.
  • FIG. 3 is a bond topology diagram of the molecule of Example 31.
  • the way to remove and add these angles and dihedral angles in the free calculation can be by scaling these angle and dihedral angle parameters, or by scaling the forces and energies calculated by two different parameters.
  • the way to calculate the free energy to remove and add these angles and dihedral angles can be thermodynamic integration, free energy perturbation or Bennet acceptance ratio.
  • the "angles and dihedral angles to be removed with the lambda value" in Table 2 should be removed from the free energy calculation, and at the same time, the table 2 should be added. "Extra dihedral angle to increase with lambda value”.
  • the free energy of removing and adding these angles and dihedral angles should be added to the total free energy.
  • the way to remove and add these angles and dihedral angles in the free calculation can be by scaling these angle and dihedral angle parameters, or by scaling the forces and energies calculated by two different parameters.
  • the way to calculate the free energy to remove and add these angles and dihedral angles can be thermodynamic integration, free energy perturbation or Bennet acceptance ratio.
  • the "angles and dihedral angles to be removed with the lambda value” in Table 3 should be removed from the free energy calculation, and the table should be added at the same time. "Additional dihedral angle to increase with lambda value” in 3.
  • the free energy of removing and adding these angles and dihedral angles should be added to the total free energy.
  • the way to remove and add these angles and dihedral angles in the free calculation can be by scaling these angle and dihedral angle parameters, or by scaling the forces and energies calculated by two different parameters.
  • the way to calculate the free energy to remove and add these angles and dihedral angles can be thermodynamic integration, free energy perturbation or Bennet acceptance ratio.

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Abstract

Provided is a relative free energy calculation method which is physically rigorous and which maximizes phase space overlap; obtaining a structure in an equilibrium state by performing NPT ensemble dynamics simulation on molecules X and Y; determining the atoms in the two molecules X and Y that correspond to each other and are to be retained, and the atoms where X is to disappear and Y is to grow; according to a rule, determining the angles and dihedral angles of X and Y, respectively, to be removed to achieve physical rigor, and the additional dihedral angles added to X and Y, respectively, to maximize the phase space overlap; removing the excess angular and dihedral effects between the atoms to disappear and to be retained on X and Y; increasing the additional dihedral angle effect to fix the structure between the atoms to disappear and the retained atoms on X and Y; statistically removing redundant angles and dihedral angles, and adding the free energy required by an additional dihedral angle, and including that part of the free energy in the total free energy of the change from X to Y. Thus the physical rigor of free energy perturbation calculation is ensured and phase space overlap is maximized.

Description

物理严格且相空间重叠最大化的相对自由能计算方法Physically Rigorous and Maximized Phase Space Overlap for Relative Free Energy Calculation 技术领域technical field
本发明属于药物设计技术领域，具体涉及一种物理严格且相空间重叠最大化的相对自由能计算方法，是针对相对自由能微扰计算的算法补充，使相对自由能微扰计算即能保证物理严格，且在此前提下又能保证相空间的重叠最大化。The invention belongs to the technical field of drug design, and in particular relates to a relative free energy calculation method with strict physics and maximum phase space overlap, which is an algorithm supplement for the relative free energy perturbation calculation, so that the relative free energy perturbation calculation can guarantee the physical Strict, and on this premise, the overlap of the phase space can be guaranteed to be maximized.
背景技术Background technique
在众多的药物设计方法中，自由能微扰计算(RBFEP)是评估药物小分子和靶点结合强度的一种基于物理的高精度方法，它可以有效的去除假阳性分子，提高设计成功率，加速新药研发的进程。基于增强采样算法，高精度分子力场(Xforce)和严谨的数据统计分析方法建立起来的FEP流程，需要在短时间内精确地计算出数百个小分子药物候选化合物和靶点的结合自由能。XFEP在数十个测试体系和一系列的实际项目中的官能团替换和骨架跃迁计算上的预测误差(mean unsigned error)均低于1.0kcal/mol，预测值和实验中得到的数据显示显著相关性。Among many drug design methods, free energy perturbation calculation (RBFEP) is a physics-based high-precision method for evaluating the binding strength of small drug molecules and targets. It can effectively remove false positive molecules and improve the design success rate. Accelerate the process of new drug development. The FEP process established based on enhanced sampling algorithm, high-precision molecular force field (Xforce) and rigorous data statistical analysis method needs to accurately calculate the binding free energy of hundreds of small molecule drug candidate compounds and targets in a short time. . The mean unsigned error (mean unsigned error) of XFEP in the calculation of functional group substitution and backbone transition in dozens of test systems and a series of real projects is less than 1.0kcal/mol, and the predicted value and the data obtained in the experiment show significant correlation .
在众多的药物设计方法中，自由能微扰计算(RBFEP)是评估药物小分子和靶点结合强度的一种基于物理的高精度方法，它可以有效的去除假阳性分子，提高设计成功率，加速新药研发的进程。基于增强采样算法，高精度分子力场(Xforce)和严谨的数据统计分析方法建立起来的FEP流程，需要在短时间内精确地计算出数百个小分子药物候选化合物和靶点的结合自由能。XFEP在数十个测试体系和一系列的实际项目中的官能团替换和骨架跃迁计算上的预测误差(mean unsigned error)均低于1.0kcal/mol，预测值和实验中得到的数据显示显著相关性。Among many drug design methods, free energy perturbation calculation (RBFEP) is a physics-based high-precision method for evaluating the binding strength of small drug molecules and targets. It can effectively remove false positive molecules and improve the design success rate. Accelerate the process of new drug development. The FEP process established based on enhanced sampling algorithm, high-precision molecular force field (Xforce) and rigorous data statistical analysis method needs to accurately calculate the binding free energy of hundreds of small molecule drug candidate compounds and targets in a short time. . The mean unsigned error (mean unsigned error) of XFEP in the calculation of functional group substitution and backbone transition in dozens of test systems and a series of real projects is less than 1.0kcal/mol, and the predicted value and the data obtained in the experiment show significant correlation .
发明内容SUMMARY OF THE INVENTION
针对上述技术问题，本发明的目的在于提供一种物理严格且相空间重叠最大化的相对自由能计算方法。In view of the above technical problems, the purpose of the present invention is to provide a method for calculating relative free energy that is physically strict and maximizes phase space overlap.
为实现上述目的，本发明提供如下技术方案：To achieve the above object, the present invention provides the following technical solutions:
物理严格且相空间重叠最大化的相对自由能计算方法，包括以下步骤：A method for calculating relative free energy that is physically rigorous and maximizes phase space overlap, including the following steps:
步骤A:将两个要计算相对自由能的分子即分子X和分子Y，进行npt系综动力学模拟过程，获得平衡态的结构；Step A: carry out the npt ensemble dynamics simulation process with two molecules to be calculated relative free energy, namely molecule X and molecule Y, to obtain the structure of the equilibrium state;
步骤B:确定X、Y两个分子中相互对应并要保留的原子，和X要消失、Y要生长的原子；根据规则确定要达到物理严格所需去除的X和Y各自的角和二面角，和为最大化相空间重叠所需增加到X和Y上的各自的额外二面角；Step B: determine the atoms corresponding to each other and to be retained in the two molecules of X and Y, and the atoms that X will disappear and Y will grow; according to the rules, determine the respective angles and two sides of X and Y that need to be removed to achieve physical strictness angle, and the respective additional dihedral angles added to X and Y to maximize phase space overlap;
步骤C:在X变化到Y的相对自由能计算中，增大lambda值，去除X上要消失的原子与保留的原子之间多余的角和二面角作用；减小lambda值，去除Y上要消失的原子与保留的原子之间多余的角和二面角作用；Step C: In the calculation of the relative free energy of the change from X to Y, increase the lambda value to remove the excess angle and dihedral angle between the atoms to be disappeared and the remaining atoms on X; decrease the lambda value and remove the effect of the The superfluous angle and dihedral effect between the atoms to be disappeared and the remaining atoms;
同时，增大lambda值，增大额外的二面角作用来固定X上要消失的原子与保留的原子之间的结构；减小lambda值，增大额外的二面角作用来固定Y上要生长的原子与保留的原子之间的结构；At the same time, increase the lambda value and increase the extra dihedral angle to fix the structure between the atoms to be disappeared and the remaining atoms on X; decrease the lambda value and increase the extra dihedral angle to fix the structure on the Y The structure between the growing and remaining atoms;
步骤D:在相对自由能计算中，统计去除多余角和二面角，以及增加额外二面角所需的自由能，并将此部分自由能计入到X到Y变化的总自由能中。Step D: In the calculation of relative free energy, the free energy required to remove excess and dihedral angles and add additional dihedral angles is statistically calculated, and this part of the free energy is included in the total free energy of the change from X to Y.
其中，步骤C中，用于固定的二面角的平衡值取自步骤A中X和Y各自的平衡后结构。Wherein, in step C, the equilibrium value of the fixed dihedral angle is taken from the respective balanced structures of X and Y in step A.
与现有技术相比，本发明的有益效果是：Compared with the prior art, the beneficial effects of the present invention are:
(1)确保相对自由能微扰计算的物理严格性；(1) Ensure the physical rigor of the relative free energy perturbation calculation;
(2)在保证自由能微扰计算的物理严格性的前提下，最大化相空间重叠；(2) Maximize phase space overlap under the premise of ensuring the physical rigor of free energy perturbation calculations;
(3)可适用于绝大多数化学变化。(3) Applicable to most chemical changes.
附图说明Description of drawings
图1为实施例1分子的键拓扑图；Fig. 1 is the bond topology diagram of the molecule of Example 1;
图2为实施例2分子的键拓扑图；Fig. 2 is the bond topology diagram of the molecule of Example 2;
图3为实施例31分子的键拓扑图。FIG. 3 is a bond topology diagram of the molecule of Example 31. FIG.
具体实施方式Detailed ways
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.
实施例1：Example 1:
在图1中，原子Cxx对应X和Y要保留的原子，原子Dxx对应X或者Y要消失或者生长的原子。R1，R2为分子的延伸。In Figure 1, atoms Cxx correspond to atoms where X and Y are to remain, and atoms Dxx correspond to atoms where X or Y are to disappear or grow. R1, R2 are extensions of the molecule.
若分子的键拓扑如图1所示，C0和Dxx原子仅通过一根建相连接。此类情况类似X或者Y要消失或者生长一个-NH2基团。若自由能计算需要去除图1中的D1，D21和D22原子，则要在自由能计算中去除表1中“要随lambda值去除的角和二面角”，并同时增加表1中“要随lambda值增加的额外二面角”。去除和增加这些角和二面角的自由能应当计入到 总的自由能中去。在自由计算中去除和增加这些角和二面角的方式可以是缩放这些角和二面角参数，也可以是缩放两个不同参数计算得到的作用力和能量。计算去除和增加这些角和二面角的自由能的方式可以是热力学积分，自由能微扰或者Bennet接受比例。If the bond topology of the molecule is shown in Figure 1, the C0 and Dxx atoms are connected by only one link. This situation is similar to the disappearance of X or Y or the growth of a -NH2 group. If the free energy calculation needs to remove the D1, D21 and D22 atoms in Figure 1, the "angle and dihedral angle to be removed with the lambda value" in Table 1 should be removed from the free energy calculation, and at the same time, the "required angle and dihedral angle to be removed with the lambda value" in Table 1 should be removed in the free energy calculation. Additional dihedral angle with lambda value". The free energy of removing and adding these angles and dihedral angles should be added to the total free energy. The way to remove and add these angles and dihedral angles in the free calculation can be by scaling these angle and dihedral angle parameters, or by scaling the forces and energies calculated by two different parameters. The way to calculate the free energy to remove and add these angles and dihedral angles can be thermodynamic integration, free energy perturbation or Bennet acceptance ratio.
表1Table 1
Figure PCTCN2020126777-appb-000001
Figure PCTCN2020126777-appb-000001
实施例2：Example 2:
在图2中，原子Cxx对应X和Y要保留的原子，原子Dxx对应X或者Y要消失或者生长的原子。R1，R2为分子的延伸。In Figure 2, atoms Cxx correspond to atoms where X and Y are to remain, and atoms Dxx correspond to atoms where X or Y are to disappear or grow. R1, R2 are extensions of the molecule.
若分子的键拓扑如图2所示，C0和Dxx原子有两根建相连接。此类情况类似X或者Y要消失或者生长一个-H外加一个-NH2基团。If the bond topology of the molecule is shown in Figure 2, the C0 and Dxx atoms have two connections. Such cases are similar to the disappearance of X or Y or the growth of a -H plus a -NH2 group.
若自由能计算需要去除图2中的D11，D12，D21和D22原子，则要在自由能计算中去除表2中“要随lambda值去除的角和二面角”，并同时增加表2中“要随lambda值增加的额外二面角”。去除和增加这些角和二面角的自由能应当计入到总的自由能中去。在自由计算中去除和增加这些角和二面角的方式可以是缩放这些角和二面角参数，也可以是缩放两个不同参数计算得到的作用力和能量。计算去除和增加这些角和二面角的自由能的方式可以是热力学积分，自由能微扰或者Bennet接受比例。If the free energy calculation needs to remove the D11, D12, D21 and D22 atoms in Figure 2, the "angles and dihedral angles to be removed with the lambda value" in Table 2 should be removed from the free energy calculation, and at the same time, the table 2 should be added. "Extra dihedral angle to increase with lambda value". The free energy of removing and adding these angles and dihedral angles should be added to the total free energy. The way to remove and add these angles and dihedral angles in the free calculation can be by scaling these angle and dihedral angle parameters, or by scaling the forces and energies calculated by two different parameters. The way to calculate the free energy to remove and add these angles and dihedral angles can be thermodynamic integration, free energy perturbation or Bennet acceptance ratio.
表2Table 2
Figure PCTCN2020126777-appb-000002
Figure PCTCN2020126777-appb-000002
Figure PCTCN2020126777-appb-000003
Figure PCTCN2020126777-appb-000003
实施例3：Example 3:
在图3中，原子Cxx对应X和Y要保留的原子，原子Dxx对应X或者Y要消失或者生长的原子。R1为分子的延伸。In Figure 3, atoms Cxx correspond to atoms for which X and Y are to remain, and atoms Dxx correspond to atoms for which X or Y are to disappear or grow. R1 is an extension of the molecule.
若分子的键拓扑如图3所示，C0和Dxx原子有三根建相连接。此类情况类似X或者Y要消失或者生长两个-H外加一个-NH2基团。If the bond topology of the molecule is shown in Figure 3, there are three connections between the C0 and Dxx atoms. Such cases are similar to the disappearance of X or Y or the growth of two -H plus one -NH2 group.
若自由能计算需要去除图2中的D11，D12，D13，D21和D22原子，则要在自由能计算中去除表3中“要随lambda值去除的角和二面角”，并同时增加表3中“要随lambda值增加的额外二面角”。去除和增加这些角和二面角的自由能应当计入到总的自由能中去。在自由计算中去除和增加这些角和二面角的方式可以是缩放这些角和二面角参数，也可以是缩放两个不同参数计算得到的作用力和能量。计算去除和增加这些角和二面角的自由能的方式可以是热力学积分，自由能微扰或者Bennet接受比例。If the free energy calculation needs to remove the D11, D12, D13, D21 and D22 atoms in Figure 2, the "angles and dihedral angles to be removed with the lambda value" in Table 3 should be removed from the free energy calculation, and the table should be added at the same time. "Additional dihedral angle to increase with lambda value" in 3. The free energy of removing and adding these angles and dihedral angles should be added to the total free energy. The way to remove and add these angles and dihedral angles in the free calculation can be by scaling these angle and dihedral angle parameters, or by scaling the forces and energies calculated by two different parameters. The way to calculate the free energy to remove and add these angles and dihedral angles can be thermodynamic integration, free energy perturbation or Bennet acceptance ratio.
表3table 3
Figure PCTCN2020126777-appb-000004
Figure PCTCN2020126777-appb-000004
Figure PCTCN2020126777-appb-000005
Figure PCTCN2020126777-appb-000005
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are more specific and detailed, but should not be construed as a limitation on the scope of the invention patent. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be subject to the appended claims.

Claims (2)

  1. 物理严格且相空间重叠最大化的相对自由能计算方法，其特征在于，包括以下步骤：A method for calculating relative free energy that is physically rigorous and maximizes phase space overlap, characterized in that it includes the following steps:
    步骤A:将两个要计算相对自由能的分子即分子X和分子Y，进行npt系综动力学模拟过程，获得平衡态的结构；Step A: carry out the npt ensemble dynamics simulation process with two molecules to be calculated relative free energy, namely molecule X and molecule Y, to obtain the structure of the equilibrium state;
    步骤B:确定X、Y两个分子中相互对应并要保留的原子，和X要消失、Y要生长的原子；根据规则确定要达到物理严格所需去除的X和Y各自的角和二面角，和为最大化相空间重叠所需增加到X和Y上的各自的额外二面角；Step B: determine the atoms corresponding to each other and to be retained in the two molecules of X and Y, and the atoms that X will disappear and Y will grow; according to the rules, determine the respective angles and two sides of X and Y that need to be removed to achieve physical strictness angle, and the respective additional dihedral angles added to X and Y to maximize phase space overlap;
    步骤C:在X变化到Y的相对自由能计算中，增大lambda值，去除X上要消失的原子与保留的原子之间多余的角和二面角作用；减小lambda值，去除Y上要消失的原子与保留的原子之间多余的角和二面角作用；Step C: In the calculation of the relative free energy of the change from X to Y, increase the lambda value to remove the excess angle and dihedral angle between the atoms to be disappeared and the remaining atoms on X; decrease the lambda value and remove the effect of the The superfluous angle and dihedral effect between the atoms to be disappeared and the remaining atoms;
    同时，增大lambda值，增大额外的二面角作用来固定X上要消失的原子与保留的原子之间的结构；减小lambda值，增大额外的二面角作用来固定Y上要生长的原子与保留的原子之间的结构；At the same time, increase the lambda value and increase the extra dihedral angle to fix the structure between the atoms to be disappeared and the remaining atoms on X; decrease the lambda value and increase the extra dihedral angle to fix the structure on the Y The structure between the growing and remaining atoms;
    步骤D:在相对自由能计算中，统计去除多余角和二面角，以及增加额外二面角所需的自由能，并将此部分自由能计入到X到Y变化的总自由能中。Step D: In the calculation of relative free energy, the free energy required to remove excess and dihedral angles and add additional dihedral angles is statistically calculated, and this part of the free energy is included in the total free energy of the change from X to Y.
  2. 根据权利要求1所述的物理严格且相空间重叠最大化的相对自由能计算方法，其特征在于，步骤C中，用于固定的二面角的平衡值取自步骤A中X和Y各自的平衡后结构。The method for calculating relative free energy with strict physics and maximizing phase space overlap according to claim 1, characterized in that, in step C, the equilibrium value of the fixed dihedral angle is taken from the respective values of X and Y in step A. Balanced structure.
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