Schmidt Thomas C, Welker Armin, Rieger Max, Sahu Prabhat K, Sotriffer Christoph A, Schirmeister Tanja, Engels Bernd
Institut für Physikalische und Theoretische Chemie, Julius-Maximilians-Universität Würzburg, Würzburg (Germany).
Chemphyschem. 2014 Oct 20;15(15):3226-35. doi: 10.1002/cphc.201402542. Epub 2014 Sep 24.
The inhibition potencies of covalent inhibitors mainly result from the formation of a covalent bond to the enzyme during the inhibition mechanism. This class of inhibitors has essentially been ignored in previous target-directed drug discovery projects because of concerns about possible side effects. However, their advantages, such as higher binding energies and longer drug-target residence times moved them into the focus of recent investigations. While the rational design of non-covalent inhibitors became standard the corresponding design of covalent inhibitors is still in its early stages. Potent covalent inhibitors can be retrieved from large compound libraries by covalent docking approaches but protocols are missing that can reliably predict the influence of variations in the substitution pattern on the affinity and/or reactivity of a given covalent inhibitor. Hence, the wanted property profile can only be obtained from trial-and-error proceedings. This paper presents an appropriate protocol which is able to predict improved covalent inhibitors. It uses hybrid approaches, which mix quantum mechanical (QM) and molecular mechanical (MM) methods to predict variations in the reactivity of the inhibitor. They are also used to compute the required information about the non-covalent enzyme-inhibitor complex. Docking tools are employed to improve the inhibitor with respect to the non-covalent interactions formed in the binding site.
共价抑制剂的抑制效力主要源于在抑制机制过程中与酶形成共价键。由于担心可能的副作用，这类抑制剂在以往的靶向药物发现项目中基本上被忽视了。然而，它们的优势，如更高的结合能和更长的药物 - 靶点驻留时间，使其成为近期研究的焦点。虽然非共价抑制剂的合理设计已成为标准，但共价抑制剂的相应设计仍处于早期阶段。可以通过共价对接方法从大型化合物库中检索出强效共价抑制剂，但缺少能够可靠预测取代模式变化对给定共价抑制剂亲和力和/或反应性影响的方案。因此，理想的性质概况只能通过反复试验的过程来获得。本文提出了一种能够预测改进的共价抑制剂的合适方案。它使用混合方法，将量子力学（QM）和分子力学（MM）方法结合起来预测抑制剂反应性的变化。这些方法还用于计算有关非共价酶 - 抑制剂复合物的所需信息。对接工具用于针对结合位点中形成的非共价相互作用来优化抑制剂。
