自由能微扰
摄动(天文学)
药物发现
化学
小分子
组合化学
计算机科学
生物物理学
计算生物学
计算化学
生物化学
物理
分子动力学
生物
量子力学
作者
Shan Sun,Makoto Fushimi,Thomas Rossetti,Navpreet Kaur,Jacob Ferreira,Michael Miller,Jonathan Quast,Joop van den Heuvel,Clemens Steegborn,Lonny R. Levin,Jochen Buck,Robert W. Myers,Stacia Kargman,Nigel J. Liverton,Peter T. Meinke,David J. Huggins
标识
DOI:10.1021/acs.jcim.2c01577
摘要
Free energy perturbation is a computational technique that can be used to predict how small changes to an inhibitor structure will affect the binding free energy to its target. In this paper, we describe the utility of free energy perturbation with FEP+ in the hit-to-lead stage of a drug discovery project targeting soluble adenyl cyclase. The project was structurally enabled by X-ray crystallography throughout. We employed free energy perturbation to first scaffold hop to a preferable chemotype and then optimize the binding affinity to sub-nanomolar levels while retaining druglike properties. The results illustrate that effective use of free energy perturbation can enable a drug discovery campaign to progress rapidly from hit to lead, facilitating proof-of-concept studies that enable target validation.
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