Structure-Based Design Technology Contour and Its Application to the Design of Renin Inhibitors

It is well-known that the structure-based design approach has had a measurable impact on the drug discovery process in identifying novel and efficacious therapeutic agents for a variety of disease targets. The de novo design approach has inherent potential to generate novel molecules that best fit into a protein binding site when compared to all of the computational methods applied to structure-based design. In its initial attempts, this approach did not achieve much success due to technical hurdles. More recently, the algorithmic advancements in the methodologies and clever strategies developed to design drug-like molecules have improved the success rate. We describe a state-of-the-art structure-based design technology called Contour and provide details of the algorithmic enhancements we have implemented. Contour was designed to create novel drug-like molecules by assembling synthetically viable fragments in the protein binding site using a high-resolution crystal structure of the protein. The technology consists of a sophisticated growth algorithm and a novel scoring function based on a directional model. The growth algorithm generates molecules by dynamically selecting only those fragments from the fragment library that are complementary to the binding site, and assembling them by sampling the conformational space for each attached fragment. The scoring function embodying the essential elements of the binding interactions aids in the rank ordering of grown molecules and helps identify those that have high probability of exhibiting activity against the protein target of interest. The application of Contour to identify inhibitors against human renin enzyme eventually leading to the clinical candidate VTP-27,999 will be discussed here.众所周知，基于结构的设计方法（structure-based design）在针对多种疾病靶点发现新型高效治疗剂的药物研发流程中，已产生了可量化的积极影响。与所有应用于基于结构设计的计算方法相比，从头设计（de novo design）方法天生具备生成可完美契合蛋白质结合位点的新型分子的潜力。该方法在初期尝试中因技术壁垒未能取得显著成效。近年来，面向类药分子设计的算法方法革新与精巧策略开发，已提升了该方法的成功率。本文介绍一款名为Contour的最先进基于结构设计技术，并详述了我们所实现的算法优化方案。Contour的设计思路是利用蛋白质的高分辨率晶体结构，在蛋白质结合位点中组装具备合成可行性的片段，以此生成新型类药分子。该技术包含一套精密的生长算法，以及一款基于定向模型的全新评分函数。该生长算法通过以下流程生成分子：从片段库中动态筛选出与结合位点互补的片段，并通过对每个连接片段的构象空间进行采样完成组装。该评分函数蕴含了结合相互作用的核心要素，可用于对生成的分子进行排序，并筛选出对目标蛋白质靶点具有较高活性概率的候选分子。本文还将讨论Contour用于鉴定人肾素酶抑制剂、最终催生出临床候选药物VTP-27,999的应用案例。