A THEORETICAL APPROACH TO DRUG DESIGN .1. RELATIVE SOLVATION THERMODYNAMICS FOR THE ANTIBACTERIAL COMPOUND TRIMETHOPRIM AND ETHYL DERIVATIVES SUBSTITUTED AT THE 3', 4', AND 5' POSITIONS

被引:25
作者
BROOKS, CL [1 ]
FLEISCHMAN, SH [1 ]
机构
[1] CONVEX COMP CORP,RICHARDSON,TX 75080
关键词
D O I
10.1021/ja00165a008
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Free energy simulation methods are used to compute the relative solvation thermodynamics of the antibacterial drug trimethoprim [2, 4-diamino-5-(3', 4',5'-trimethoxybenzyl)pyrimidine] and a family of congeners derived from methoxy → ethyl substitution on the benzyl ring. The aqueous solubility is found to decrease as more hydrophobic character is introduced into the parent molecule. Nearly additive effects on the solvation free energy are observed for the mono- and disubstituted derivatives, with exception of the 3',5'-diethyl derivative. This compound shows an increased aqueous solubility (over that of the other diethyl compound), which is linked to anomalous entropic effects of the p-methoxy group. The triethyl-substituted molecule exhibits a similar solvation free energy to that of the 3', 4'-diethyl compound, which appears as additive contributions from the 3',5'-diethyl and 4'-monoethyl derivatives. © 1990, American Chemical Society. All rights reserved.
引用
收藏
页码:3307 / 3312
页数:6
相关论文
共 20 条
[11]   RECEPTOR-BASED DESIGN OF DIHYDROFOLATE-REDUCTASE INHIBITORS - COMPARISON OF CRYSTALLOGRAPHICALLY DETERMINED ENZYME BINDING WITH ENZYME AFFINITY IN A SERIES OF CARBOXY-SUBSTITUTED TRIMETHOPRIM ANALOGS [J].
KUYPER, LF ;
ROTH, B ;
BACCANARI, DP ;
FERONE, R ;
BEDDELL, CR ;
CHAMPNESS, JN ;
STAMMERS, DK ;
DANN, JG ;
NORRINGTON, FE ;
BAKER, DJ ;
GOODFORD, PJ .
JOURNAL OF MEDICINAL CHEMISTRY, 1985, 28 (03) :303-311
[12]  
LI RL, 1982, QUANT STRUCT-ACT REL, V1, P1
[13]  
MATTHEWS DA, 1985, J BIOL CHEM, V260, P392
[14]  
MATTHEWS DA, 1985, J BIOL CHEM, V260, P381
[15]  
RYCHAERT JP, 1977, J COMPUT PHYS, V23, P327
[16]   STATISTICAL ERRORS IN MOLECULAR-DYNAMICS AVERAGES [J].
SCHIFERL, SK ;
WALLACE, DC .
JOURNAL OF CHEMICAL PHYSICS, 1985, 83 (10) :5203-5209
[18]   A FREE-ENERGY PERTURBATION STUDY OF THE BINDING OF METHOTREXATE TO MUTANTS OF DIHYDROFOLATE-REDUCTASE [J].
SINGH, UC ;
BENKOVIC, SJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (24) :9519-9523
[19]   LIGAND RECEPTOR INTERACTIONS [J].
TEMBE, BL ;
MCCAMMON, JA .
COMPUTERS & CHEMISTRY, 1984, 8 (04) :281-283
[20]  
[No title captured]