FURTHER DEVELOPMENT OF HYDROGEN-BOND FUNCTIONS FOR USE IN DETERMINING ENERGETICALLY FAVORABLE BINDING-SITES ON MOLECULES OF KNOWN STRUCTURE .1. LIGAND PROBE GROUPS WITH THE ABILITY TO FORM 2 HYDROGEN-BONDS

被引:192
作者
WADE, RC [1 ]
CLARK, KJ [1 ]
GOODFORD, PJ [1 ]
机构
[1] UNIV OXFORD, MOLEC BIOPHYS LAB, OXFORD OX1 3QU, ENGLAND
关键词
D O I
10.1021/jm00053a018
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The directional properties of hydrogen bonds play a major role in determining the specificity of intermolecular interactions. An energy function which takes explicit account of these properties has been developed for use in the determination of energetically favorable ligand binding sites on molecules of known structure by the GRID method (Goodford, P. J. J. Med. Chem. 1985, 28,849. Boobbyer, D. N. A.; Goodford, P. J.; McWhinnie, P. M.; Wade, R. C. J. Med. Chem. 1989, 32, 1083). In this method, the interaction energy between a target molecule and a small chemical group (a probe), which may be part of a larger ligand, was calculated using an energy function of Lennard-Jones, electrostatic, and hydrogen bond terms. The latter term was a function of the length of the hydrogen bond, its orientation at the hydrogen-bonding atoms, and their chemical nature. We now describe hydrogen bond energy functions which take account of the spatial distribution of the hydrogen bonds made by probes with the ability to form two hydrogen bonds. These functions were designed so as to model the experimentally observed angular dependence of the hydrogen bonds. We also describe the procedure to locate the position and orientation of the probe at which the interaction energy is optimized. The use of this procedure is demonstrated by examples of biological and pharmacological interest which show that it can produce results that are consistent with other theoretical approaches and with experimental observations.
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页码:140 / 147
页数:8
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