Assessing the performance of docking, FEP, and MM/GBSA methods on a series of KLK6 inhibitors

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Wemenes José Lima Silva, Renato Ferreira de Freitas
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Abstract

Kallikrein 6 (KLK6) is an attractive drug target for the treatment of neurological diseases and for various cancers. Herein, we explore the accuracy and efficiency of different computational methods and protocols to predict the free energy of binding (ΔGbind) for a series of 49 inhibitors of KLK6. We found that the performance of the methods varied strongly with the tested system. For only one of the three KLK6 datasets, the docking scores obtained with rDock were in good agreement (R2 ≥ 0.5) with experimental values of ΔGbind. A similar result was obtained with MM/GBSA (using the ff14SB force field) calculations based on single minimized structures. Improved binding affinity predictions were obtained with the free energy perturbation (FEP) method, with an overall MUE and RMSE of 0.53 and 0.68 kcal/mol, respectively. Furthermore, in a simulation of a real-world drug discovery project, FEP was able to rank the most potent compounds at the top of the list. These results indicate that FEP can be a promising tool for the structure-based optimization of KLK6 inhibitors.

Abstract Image

评估对接、FEP和MM/GBSA方法对一系列KLK6抑制剂的性能
Kallikrein 6 (KLK6)是治疗神经系统疾病和各种癌症的一个有吸引力的药物靶点。在此,我们探索了不同的计算方法和协议的准确性和效率,以预测49种KLK6抑制剂的自由结合能(ΔGbind)。我们发现,这些方法的性能随测试系统的不同而有很大的变化。在三个KLK6数据集中,只有一个数据集使用rDock获得的对接得分与实验值ΔGbind符合较好(R2≥0.5)。基于单个最小化结构的MM/GBSA(使用ff14SB力场)计算得到了类似的结果。利用自由能摄动(FEP)方法得到了更好的结合亲和力预测,总体MUE和RMSE分别为0.53和0.68 kcal/mol。此外,在模拟真实世界的药物发现项目中,FEP能够将最有效的化合物排在列表的顶部。这些结果表明,FEP可以作为KLK6抑制剂结构优化的一个有前途的工具。
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来源期刊
Journal of Computer-Aided Molecular Design
Journal of Computer-Aided Molecular Design 生物-计算机:跨学科应用
CiteScore
8.00
自引率
8.60%
发文量
56
审稿时长
3 months
期刊介绍: The Journal of Computer-Aided Molecular Design provides a form for disseminating information on both the theory and the application of computer-based methods in the analysis and design of molecules. The scope of the journal encompasses papers which report new and original research and applications in the following areas: - theoretical chemistry; - computational chemistry; - computer and molecular graphics; - molecular modeling; - protein engineering; - drug design; - expert systems; - general structure-property relationships; - molecular dynamics; - chemical database development and usage.
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