title: Segmental analysis of molecular surface electrostatic potentials: application to enzyme inhibition.
abstract: We have recently shown that the anti-HIV activities of reverse transcriptase inhibitors can be related quantitatively to properties of the electrostatic potentials on their molecular surfaces. We now introduce the technique of using only segments of the drug molecules in developing such expressions. If an improved correlation is obtained for a given family of compounds, it would suggest that the segment being used plays a key role in the interaction. We demonstrate the procedure for three groups of drugs, two acting on reverse transcriptase and one on HIV protease. Segmental analysis is found to be definitely beneficial in one case, less markedly so in another, and to have a negative effect in the third. The last result indicates that major portions of the molecular surfaces are involved in the interactions and that the entire molecules need to be considered, in contrast to the first two examples, in which certain segments appear to be of primary importance. This initial exploratory study shows that segmental analysis can provide insight into the nature of the process being investigated, as well as possibly enhancing the predictive capability.
authors.affiliation: Department of Physical Chemistry, Royal Institute of Technology, 100 44, Stockholm, Sweden.
authors.forename: Tore
authors.initials: T
authors.lastname: Brinck
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Ma
authors.forename: Jane S
authors.initials: JS
authors.lastname: Murray
authors.forename: Peter
authors.initials: P
authors.lastname: Politzer
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D002261:Carboxin / Q000031:analogs & derivatives / Q000737:chemistry; D003486:Cyanides / Q000737:chemistry; D006146:Guanidines / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry*; D055672:Static Electricity; D013329:Structure-Activity Relationship
chemical_list: D003486:Cyanides; D006146:Guanidines; D017320:HIV Protease Inhibitors; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D018894:Reverse Transcriptase Inhibitors; D002261:Carboxin; D054303:HIV Reverse Transcriptase; D016333:HIV Protease; C004479:pimagedine