THE MATCHING OF ELECTROSTATIC EXTREMA - A USEFUL METHOD IN DRUG DESIGN - A STUDY OF PHOSPHODIESTERASE-III INHIBITORS

被引:34
作者
APAYA, RP [1 ]
LUCCHESE, B [1 ]
PRICE, SL [1 ]
VINTER, JG [1 ]
机构
[1] UCL, DEPT CHEM, LONDON WC1H 0AJ, ENGLAND
关键词
DISTRIBUTED MULTIPOLES; ELECTROSTATIC SIMILARITY; RELATIVE BINDING ORIENTATION; PHOSPHODIESTERASE INHIBITORS;
D O I
10.1007/BF00117276
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
Ligands which bind to a specific protein binding site are often expected to have a similar electrostatic environment which complements that of the binding site. One method of assessing molecular electrostatic similarity is to examine the possible overlay of the maxima and minima in the electrostatic potential outside the molecules and thereby match the regions where strong electrostatic interactions, including hydrogen bonds, with the residues of the binding site may be possible. This approach is validated with accurate calculations of the electrostatic potential, derived from a distributed multipole analysis of an ab initio charge density of the molecule, so that the effects of lone pair and pi-electron density are correctly included. We have applied this method to the phosphodiesterase (PDE) III substrate adenosine-3',5'-cyclic monophosphate (cAMP) and a range of nonspecific and specific PDE III inhibitors. Despite the structural variation between cAMP and the inhibitors, it is possible to match three or four extrema to produce relative orientations in which the inhibitors are sufficiently sterically and electrostatically similar to the natural substrate to account for their affinity for PDE III. This matching of extrema is more apparent using the accurate electrostatic models than it was when this approach was first applied, using semiempirical point charge models. These results reinforce the hypothesis of electrostatic similarity and give weight to the technique of extrema matching as a useful tool in drug design.
引用
收藏
页码:33 / 43
页数:11
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