二肽基肽酶1（DPP1）抑制剂：利用取代吡咯烷探究水在DPP1的S2口袋中的作用。
DPP1 Inhibitors: Exploring the Role of Water in the S2 Pocket of DPP1 with Substituted Pyrrolidines.
作者信息
Käck Helena, Doyle Kevin, Hughes Samantha J, Bodnarchuk Michael S, Lönn Hans, Van De Poël Amanda, Palmer Nicholas
机构信息
Structure, Biophysics and Fragments, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden.
Charles River Discovery Services, Cambridge, U.K.
出版信息
ACS Med Chem Lett. 2019 Jul 15;10(8):1222-1227. doi: 10.1021/acsmedchemlett.9b00261. eCollection 2019 Aug 8.
Abstract
A series of pyrrolidine amino nitrile DPP1 inhibitors have been developed and characterized. The S2 pocket structure-activity relationship for these compounds shows significant gains in potency for DPP1 from interacting further with target residues and a network of water molecules in the binding pocket. Herein we describe the X-ray crystal structures of several of these compounds alongside an analysis of factors influencing the inhibitory potency toward DPP1 of which stabilization of the water network, demonstrated using Grand Canonical Monte Carlo simulations and free energy calculations, is attributed as a main factor.
摘要
一系列吡咯烷氨基腈类DPP1抑制剂已被开发并表征。这些化合物的S2口袋结构-活性关系表明，通过与结合口袋中的靶标残基和水分子网络进一步相互作用，DPP1的活性有显著提高。在此，我们描述了其中几种化合物的X射线晶体结构，并分析了影响对DPP1抑制活性的因素，其中通过巨正则蒙特卡罗模拟和自由能计算证明的水网络稳定被认为是一个主要因素。
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