QSAR modeling of HIV-1 reverse transcriptase inhibitor 2-amino-6-arylsulfonylbenzonitriles and congeners using molecular connectivity and E-state parameters.
Anti-HIV-1 activity (assayed in MT-4 cell line) and HIV-1 reverse transcriptase (RT) binding affinity of 2-amino-6-arylsulfonylbenzonitriles and their thio and sulfinyl congeners (Chan et al., J. Med. Chem., 2001, 44, 1866) have been modeled using E-state index along with molecular connectivity and indicator parameters in an attempt to explore the different fragments of the molecules contributing significantly to the activities. Stepwise multiple regression procedure was adopted to develop the topological models. The models generated were of acceptable statistical quality and predictive potential. The results show that for both the response variables, first order fragmental valence molecular connectivity of the meta substituents of the aryl ring plays a significant role: second meta substituents show supraadditive action on the activities probably due to enhanced binding (presumably through dispersion interaction) of the ligand with the binding site. Again, presence of sulfone moiety contributes significantly to the activities. Further, presence of meta-trifluoromethyl group at the aryl ring is detrimental for both the activity parameters. Additionally, the anti-HIV-1 model shows specific contributions of the E-state values of different atoms and positive contribution of the ortho-methoxy group present on the aryl ring.
Roy
Kunal
K
Drug Theoretics & Cheminformatics Lab, Division of Medicinal & Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India. kunalroy_in@yahoo.com
Leonard
J Thomas
JT
D000586:Amination; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013455:Sulfur / Q000737:chemistry*
D009570:Nitriles; D018894:Reverse Transcriptase Inhibitors; D013455:Sulfur; C014356:benzonitrile; D054303:HIV Reverse Transcriptase