Integrating virtual screening in lead discovery

被引:192
作者
Oprea, TI
Matter, H
机构
[1] Univ New Mexico, Sch Med, Div Biocomp, Albuquerque, NM 87131 USA
[2] Aventis Pharma Deutschland GmbH, DI&A Chem, D-65926 Frankfurt, Germany
关键词
D O I
10.1016/j.cbpa.2004.06.008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Target- and ligand-based virtual screening have emerged as resource-saving techniques that have been successfully applied to identify novel chemotypes in biologically active molecules. Eight confirmed virtual screening hits have recently been described and are discussed in this review, with focus on the workflow. These are then evaluated in the light of pharmacokinetics prediction (e.g. Caco-2 permeability, cytochrome P450 inhibition and hERG binding). We anticipate problems for five of these hits (e.g. cardiac toxicity), which warrant further experiments. Future challenges include dynamic tautomer/protonation treatment for both ligands and targets and improved pre- and post- virtual screening filters.
引用
收藏
页码:349 / 358
页数:10
相关论文
共 90 条
[1]   The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship [J].
Abraham, MH ;
Le, J .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1999, 88 (09) :868-880
[2]   Computational methods to predict binding free energy in ligand-receptor complexes [J].
Ajay ;
Murcko, MA .
JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (26) :4953-4967
[3]   EPITHELIAL TRANSPORT OF DRUGS IN CELL-CULTURE .1. A MODEL FOR STUDYING THE PASSIVE DIFFUSION OF DRUGS OVER INTESTINAL ABSORPTIVE (CACO-2) CELLS [J].
ARTURSSON, P .
JOURNAL OF PHARMACEUTICAL SCIENCES, 1990, 79 (06) :476-482
[4]   The Protein Data Bank [J].
Berman, HM ;
Westbrook, J ;
Feng, Z ;
Gilliland, G ;
Bhat, TN ;
Weissig, H ;
Shindyalov, IN ;
Bourne, PE .
NUCLEIC ACIDS RESEARCH, 2000, 28 (01) :235-242
[5]  
BEUSEN DD, 2000, PHARMACOPHORE PERCEP, P21
[6]   Hit and lead generation:: Beyond high-throughput screening [J].
Bleicher, KH ;
Böhm, HJ ;
Müller, K ;
Alanine, AI .
NATURE REVIEWS DRUG DISCOVERY, 2003, 2 (05) :369-378
[7]   Prediction of binding constants of protein ligands: A fast method for the prioritization of hits obtained from de novo design or 3D database search programs [J].
Bohm, HJ .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1998, 12 (04) :309-323
[9]   New methods in predictive metabolism [J].
Boyer, S ;
Zamora, I .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2002, 16 (5-6) :403-413
[10]   Virtual screening for submicromolar leads of tRNA-guanine transglycosylase based on a new unexpected binding mode detected by crystal structure analysis [J].
Brenk, R ;
Naerum, L ;
Grädler, U ;
Gerber, HD ;
Garcia, GA ;
Reuter, K ;
Stubbs, MT ;
Klebe, G .
JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (07) :1133-1143