Reliable gas-phase tautomer equilibria of drug-like molecule scaffolds and the issue of continuum solvation

IF 3 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Andreas H. Göller
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引用次数: 4

Abstract

Accurate calculation of relative tautomer energies in different environments is a prerequisite to many parameters of relevance in drug discovery. This work provides a thorough benchmark of the semiempirical methods AM1, PM3 and GFN2-xTB, the force-field OPLS4, Hartree–Fock and HF-3c, the density functionals PBEh-3c, B97-3c, r2SCAN-3c, PBE, PBE0, TPSS, r2SCAN, ω-B97X-V, M06-2X, B3LYP, B2PLYP, and second-order perturbation theory MP2 versus the gold-standard coupled-cluster DLPNO-CCSD(T) using the def2-QZVPP basis set. The outperforming method identified is M06-2X, whereas r2SCAN-3c is the best-perfoming one in the set of cost-optimized methods. Application of the two methods on a challenging subset from the SAMPL2 challenge provides evidence that deviations from experiment are caused by deficiencies of current continuum solvation methods.

Abstract Image

类药物分子支架的可靠气相互变异构平衡和连续溶剂化问题
准确计算不同环境下互变异构体的相对能量是药物发现中许多相关参数的先决条件。本文利用def2-QZVPP基集,对半经验方法AM1、PM3和GFN2-xTB、力场OPLS4、hartref - fock和HF-3c、密度泛函phh -3c、B97-3c、r2SCAN-3c、PBE、PBE0、TPSS、r2SCAN、ω-B97X-V、M06-2X、B3LYP、B2PLYP和二阶微动理论MP2与金标准耦合簇DLPNO-CCSD(T)进行了全面的基准测试。在成本优化方法集合中,性能最佳的方法是M06-2X,而性能最佳的方法是r2SCAN-3c。这两种方法在SAMPL2挑战的挑战性子集上的应用证明,实验偏差是由当前连续介质溶剂化方法的缺陷引起的。
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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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