Classical QSAR Modeling of HIV-1 Reverse Transcriptase Inhibitor 2-Amino-6-arylsulfonylbenzonitriles and Congeners J. Thomas Leonard and Kunal Roy* Drug Theoretics & Cheminformatics Lab, Division of Medicinal & Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032 (INDIA), E-mail: kunalroy_in@yahoo.com, URL: http://www.geocities.com/ kunalroy_in Full Paper Considering the recent interests in the development of novel and potent non-nucleoside reverse transcriptase inhibitorsforthetreatmentofHIV-1infection,anti-HIV-1 activity (assayed in MT-4 cell line) and HIV-1 reverse transcriptase (RT) binding affinity of 2-amino-6-arylsulfo- nylbenzonitriles and their thio and sulfinyl congeners (Chan et al., J. Med. Chem., 2001, 44, 1866±1882) have been modeled using classical Quantitative Structure-Ac- tivityRelationship(QSAR)toolsinanattempttoexplore the quantitative contribution pattern of different substitu- ents in the aryl ring to the activities. Different physico- chemical parameters like hydrophobicity (p), electronic (Hammett s) and steric (molar refractivity MR) terms have been used along with appropriate indicator and/or integer variables to develop linear free energy related (LFER) model. Additionally, electrostatic potential point charges at different common atoms of the molecules calculated from AM1 optimized energy minimized geom- etry have also been tried as predictor variables. The modelsgeneratedwereofacceptablestatisticalqualityand predictive potential. The results show that for both response variables, presence of sulfone moiety contributes significantly to the activities. Further, molar refractivity of meta substituentsplaysasignificantroleinboththecases: second meta substituents potentiate the activities probably due to enhanced binding (presumably through dispersion interaction) of the ligand with the binding site. Again, presence of meta-trifluoromethyl group at the aryl ring is detrimental for both the activities. Additionally, the anti- HIV-1 model shows negative contribution of the steric parameterof para substituentsandpositivecontributionof the ortho-methoxy group. 1 Introduction The Acquired Immuno Deficiency Syndrome (AIDS) epidemic has claimed more than 3 million lives in 2002, andanestimated5millionpeoplehaveacquiredthehuman immunodeficiency virus (HIV) in 2002, bringing to 42 millionthenumberofpeoplegloballylivingwiththevirus [1].HIV/AIDShasbecomethemostdevastatingpandemic intherecordedhistory.Ithaskilled40millionpeopleinthe last20yearsandtheWorldHealthOrganizationestimated thattherewouldbeupto100millionnewinfectionsinthe next10years[2]. HIV-1isanenvelopedvirus[3],whichcontainsanouter lipid bilayer, consists of two viral glycoproteins, external gp120 and the transmembrane gp41. Beneath this outer envelope is a membrane-associated protein p18, which provides a matrix for the viral structure. This matrix surrounds a characteristic dense, cylindrical nucleoid con- tainingcapsidproteinp24.Insidethisnucleoidtwoidentical RNA strands are present, with which the viral RNA- dependent DNA polymerase (pol) p66/p55, called reverse transcriptase, is in association with nucleoprotein p9, integraseproteinp12,andproteasep15components. Inarecentpaper,Garg etal.[4]havenicelyreviewedthe life cycle of HIV and different classes of anti-HIV drugs actingindifferentstagesofvirallifecycle.HIVlifecycle[3] starts with high-affinity binding of gp120 (viral glycopro- tein)envelopeproteintoitsreceptorCD4onthehostcell surface. A truncated CD4 (sCD4) molecule is capable of QSAR Comb. Sci. 2004, 23 DOI: 10.1002/qsar.200330845 ¹ 2004 WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim 23 * To receive all correspondence Key words: QSAR, AM1 calculations, Anti-HIV-1 activity, HIV- RT binding affinity, 2-amino-6-arylsulfonylbenzonitriles Abbreviations: Quantitative structure-activity relationships (QSAR); Acquired immuno deficiency syndrome (AIDS); Hu- man immunodeficiency virus (HIV); Linear free energy related (LFER); Reverse transcriptase (RT); Nucleoside reverse tran- scriptaseinhibitors(NRTIs);Non-nucleosidereversetranscriptase inhibitors (NNRTIs), Austin model 1 (AM1); Molar refractivity (MR) Classical QSAR Modeling of HIV-1 Reverse Transcriptase Inhibitor 2-Amino-6-arylsulfonylbenzonitriles and ... & Combinatorial Science