CONFORMATIONAL-ANALYSIS, MOLECULAR MODELING, AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF AGENTS FOR THE INHIBITION OF ASTROCYTIC CHLORIDE TRANSPORT
Cl. Waller et al., CONFORMATIONAL-ANALYSIS, MOLECULAR MODELING, AND QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP STUDIES OF AGENTS FOR THE INHIBITION OF ASTROCYTIC CHLORIDE TRANSPORT, Pharmaceutical research, 11(1), 1994, pp. 47-53
Molecular modeling studies were carried out on a series of 1-oxoisoind
olines which are pharmacologically active as inhibitors of astrocytic
chloride transport. Conformational analysis revealed that the halogen
substituent exerted a pronounced steric directing effect on the acid s
ide chain. The 4-substituted analogs apparently provided for the best
spatial arrangement of pharamacophoric elements of the molecules. Conv
entional quantitative structure-activity relationship (QSAR) studies u
sing lipophilic and dipole moment characteristics of the molecules as
physical descriptor variables in the regression equation yielded a sta
tistically significant model. Comparative molecular field analysis (Co
MFA) was utilized as a three-dimensional QSAR technique to explore cha
nge in the steric and electrostatic fields of the molecules that can a
ccount for differences in biological activity values. A highly predict
ive model was attained which supported the results from the qualitativ
e and conventional quantitative structure-activity relationship analys
es. These modeling techniques represent the evolutionary process by wh
ich structure-activity methods were employed to aid in the development
of novel more potent inhibitors of astrocytic chloride transport.