PROLIX: Rapid Mining of Protein鈥揕igand Interactions in Large Crystal Structure Databases

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• 作者：Martin Weisel ; Hans-Marcus Bitter ; Fran莽ois Diederich ; W. Venus So ; Rama Kondru
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2012
• 出版时间：June 25, 2012
• 年：2012
• 卷：52
• 期：6
• 页码：1450-1461
• 全文大小：516K
• 年卷期：v.52,no.6(June 25, 2012)
• ISSN：1549-960X

文摘

A central problem in structure-based drug design is understanding protein鈥搇igand interactions quantitatively and qualitatively. Several recent studies have highlighted from a qualitative perspective the nature of these interactions and their utility in drug discovery. However, a common limitation is a lack of adequate tools to mine these interactions comprehensively, since exhaustive searches of the protein data bank are time-consuming and difficult to perform. Consequently, fundamental questions remain unanswered: How unique or how common are the protein鈥搇igand interactions observed in a given drug design project when compared to all complexed structures in the protein data bank? Which interaction patterns might explain the affinity of a tool compound toward unwanted targets? To answer these questions and to enable the systematic and comprehensive study of protein鈥搇igand interactions, we introduce PROLIX (Protein Ligand Interaction Explorer), a tool that uses sophisticated fingerprint representations of protein鈥搇igand interaction patterns for rapid data mining in large crystal structure databases. Our implementation strategy pursues a branch-and-bound technique that enables mining against thousands of complexes within a few seconds. Key elements of PROLIX include (i) an intuitive interface that enables users to formulate complex queries easily, (ii) exceptional speed for results retrieval, and (iii) a sophisticated results summarization. Herein we describe the algorithms developed to enable complex queries and fast retrieval of search results, as well as the intuitive aspects of the user interface and summarization viewer.