首页 | 本学科首页   官方微博 | 高级检索  
     检索      


Methodological developments and strategies for a fast flexible superposition of drug-size molecules
Authors:Gerhard Klebe  Thomas Mietzner  Frank Weber
Institution:(1) BASF AG, Hauptlaboratorium, D-67056 Ludwigshafen, Germany
Abstract:An alternative to experimental high through-put screening is the virtual screening of compound libraries on the computer. In absence of a detailed structure of the receptor protein, candidate molecules are compared with a known reference by mutually superimposing their skeletons and scoring their similarity. Since molecular shape highly depends on the adopted conformation, an efficient conformational screening is performed using a knowledge-based approach. A comprehensive torsion library has been compiled from crystal data stored in the Cambridge Structural Database. For molecular comparison a strategy is followed considering shape associated physicochemical properties in space such as steric occupancy, electrostatics, lipophilicity and potential hydrogen-bonding. Molecular shape is approximated by a set of Gaussian functions not necessarily located at the atomic positions. The superposition is performed in two steps: first by a global alignment search operating on multiple rigid conformations and then by conformationally relaxing the best scored hits of the global search. A normalized similarity scoring is used to allow for a comparison of molecules with rather different shape and size. The approach has been implemented on a cluster of parallel processors. As a case study, the search for ligands binding to the dopamine receptor is given.
Keywords:knowledge-based conformational search  molecular similarity  molecular superposition  torsional library  virtual screening
本文献已被 PubMed SpringerLink 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号