QSAR analysis of a set of benzothiopyranoindazole anti-cancer analogs based upon their DNA intercalation properties as determined by molecular dynamics simulation.
The global low-energy intercalation thermodynamic properties for a set of 14 benzothiopyranoindazole (BTPI) analogs, determined by molecular dynamics (MD) simulation, were used as descriptors in a quantitative structure-activity relationship (QSAR) analysis to describe their observed anti-cancer activities. The calculated free-space binding (intercalation) energies by themselves, or in combination with ligand lipophilicity, do not yield significant QSARs. However, the free-space binding energy combined with the aqueous desolvation energy of the intercalation complex leads to a highly significant QSAR. The optimum QSAR corresponds to both the ligand and DNA model being charged, and a molecular dielectric of 40 used in the force field. The desolvation energy is computed using a hydration-shell model. The QSAR suggests that anti-cancer activity can be enhanced by increasing the intercalating free-space binding energy and/or decreasing the loss in the favorable hydration energies of both the ligand and DNA when intercalation occurs.
Hopfinger
A J
AJ
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago 60680.
Kawakami
Y
Y
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D007191:Indazoles; D007364:Intercalating Agents