Combinatorial design of nonsymmetrical cyclic urea inhibitors of aspartic protease of HIV-1

被引:23
作者
Frecer, V
Burello, E
Miertus, S
机构
[1] UNIDO, Int Ctr Sci & High Technol, I-34012 Trieste, Italy
[2] Slovak Acad Sci, Canc Res Inst, SK-83391 Bratislava, Slovakia
[3] Univ Trieste, Dept Biochem Biophys & Macromol Chem, I-34127 Trieste, Italy
关键词
inhibitor design; aspartic protease of HIV; library of nonsymmetrical cyclic ureas; structure-based focusing; in silico screening; ADME properties;
D O I
10.1016/j.bmc.2005.06.026
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
The aspartic protease (PR) of the human immunodeficiency virus type 1 (HIV-1) is an important target for the design of specific antiviral agents dedicated to treatment of HIV-1 infection. We have employed computer-assisted combinatorial chemistry methods to design a small focused virtual library of nonsymmetrically substituted cyclic urea inhibitors of the PR. Nonsymmetrical compounds with decreased peptidic character were namely found to inhibit the PR with comparable inhibition potencies as their C-2-pseudosymmetric counterparts and to possess superior pharmacokinetic properties. To generate the virtual library of fully nonsymmetrical cyclic urea analogs, diverse reagents were selected from databases of available chemicals with characteristics similar to those of the building blocks of known potent PR inhibitors. The X-ray structure of the protease-inhibitor complex PR XV-638 was used as the receptor model in the structure-based focusing and in silico screening of the virtual library. A target-specific LUDI-type scoring function, parameterized for a QSAR training set of known cyclic urea inhibitors and validated on a set of compounds not included into the training set, was used to predict the inhibition constants (K) of the generated analogs toward the HIV-1 PR. The fragments most frequently occurring in the analogs with the highest predicted inhibition potencies (K-i(*) < 10 pM) were then selected to constitute a highly focused library subset containing novel nonsymmetrical cyclic ureas with predicted K(i)(*)s 1 order of magnitude lower than the most potent known cyclic urea inhibitors. ADME properties calculated for the most promising analogs suggested that the cyclic ureas are endowed with a wide range of favorable pharmacokinetic properties, which may favor the discovery of a potent orally administrable antiviral drug. (c) 2005 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5492 / 5501
页数:10
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