Schoenmaker Linde, Jiskoot Daan A, Scheen Jenke, Cheng Evien, Gapsys Vytautas, Hahn David F, Ries Benjamin, van Westen Gerard J P, Mobley David L, Jespers Willem
Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Department of Pharmaceutical Sciences, University of California, Irvine, California 92697, United States.
J Phys Chem B. 2025 Mar 6;129(9):2370-2379. doi: 10.1021/acs.jpcb.4c07156. Epub 2025 Feb 20.
Alchemical free energy calculations are becoming an increasingly prevalent tool in drug discovery efforts. Over the past decade, significant progress has been made in automating various aspects of this technique. However, one aspect hampering wider application is the construction of perturbation networks to connect ligands of interest. More specifically, ligand pairs with large dissimilarities should be avoided since they can lower convergence and decrease accuracy. Here, we propose a technique for automatic generation of intermediate molecules to break up problematic edges─calculations connecting two different ligands or molecules─into smaller perturbations. To this end, a modular tool was developed that generates intermediates for a molecule pair by enumerating R-group combinations called IMERGE-FEP (Intermediate MolEculaR GEnerator for Free Energy Perturbation). Intermediate enumeration of multiple, representative congeneric series showed that intermediates increase similarity regarding shared substructures, geometry, and LOMAP scores. Taken together, this tool eases integration of intermediate steps into free energy calculation protocols.
炼金术自由能计算正日益成为药物发现工作中一种普遍使用的工具。在过去十年里，这项技术的各个方面在自动化方面都取得了重大进展。然而，阻碍其更广泛应用的一个方面是构建微扰网络以连接感兴趣的配体。更具体地说，应避免具有较大差异的配体对，因为它们会降低收敛性并降低准确性。在此，我们提出了一种自动生成中间分子的技术，以将有问题的边（连接两个不同配体或分子的计算）分解为较小的微扰。为此，开发了一种模块化工具，通过枚举称为IMERGE-FEP（用于自由能微扰的中间分子生成器）的R-基团组合来为分子对生成中间体。对多个具有代表性的同系物系列进行中间体枚举表明，中间体在共享子结构、几何形状和LOMAP评分方面增加了相似性。综上所述，该工具简化了将中间步骤整合到自由能计算协议中的过程。
