Common binding mode for structurally and chemically diverse non-nucleosidic HIV-1RT inhibitors Arpita Yadav * , Sanjeev Kumar Singh Department of Chemistry, Institute of Engineering and Technology, CSJM University, Kanpur 208024, India Received 18 August 2004; accepted 12 October 2004 Available online 9 April 2005 Abstract In this study we have performed ab initio M.O. calculations on some selected potent non-nucleosidic reverse transcriptase inhibitors. Our results indicate a bent or ‘V’-shaped conformation for each non-nucleosidic inhibitor. Our conformational mapping studies identify an amide group in each drug in an appropriate position to help anchor the drug to the biding site via lys 101; thus suggesting common binding mode for structurally, chemically diverse non-nucleosidic drugs. The molecular electrostatic potential maps predict a slightly positively charged complementary environment on the receptor. q 2004 Elsevier B.V. All rights reserved. Keywords: NNRTI’s binding mode; HF 6-31G; MESP; Conformational mapping 1. Introduction A lot of effort is being made worldwide to find effective drugs for the deadly disease AIDS [1]. AIDS is caused by the spread of human immuno deficiency virus. Many enzymatic reactions are involved in the replication of this virus. Reverse transcriptase is one such enzyme, which catalyzes the conversion of RNA retroviral genome into proviral DNA [2]. Significant efforts have been made to design inhibitors for RT resulting in the control of virus and hence the disease. RT inhibitors may be classified into two categories: nucleosidic inhibitors and non-nucleosidic inhibitors. Both are currently clini- cally employed in the treatment of AIDS either separately or through combination therapy. For example some clinically used combinations are: nevirapineC stavudineCdidanasine (effective) and efavirenzCstavudi- neCdidanasine [3]. The nucleosidic inhibitors are intracellularly converted into their triphosphate deriva- tives and act as DNA chain terminating analogs of the natural deoxynucleoside triphosphates. Hence, nucleosidic drugs undergo competitive inhibition. The non-nucleosidic inhibitors directly inhibit enzyme RT, non-competitively, upon binding to an allosteric site located about 10 A ˚ from the normal substrate dNTP binding site i.e. the polymerase catalytic site [4]. Although the nucleosidic drugs are sure to work but they induce cytotoxicity and are less selective. Another problem being the emergence of resistant mutants [5]. Hence, the structu- rally diverse set of compounds emerged as attractive targets due to their low cytotoxicity and high selectivity [6]. But this set of compounds referred to as non-nucleosidic reverse transcriptase inhibitors (NNRTI’s) often show poor bioavail- ability and pharmacokinetics and are generally used in combination therapy. In the present work we have studied some structurally and chemically diverse, potent NNRTI’s (c.f. Fig. 1) through a quantum pharmacological procedure, which has been described in detail in Ref. 7. The aim of present study is to extract common conformational and electrostatic features responsible for the binding and activity of these compounds that is, the pharmacophoric features. 2. Methodology We have performed ab initio molecular orbital calcu- lations on the compounds shown in Fig. 1a at the Hartree Fock (HF) level utilizing a 6-31G basis set [8]. Complete 0166-1280/$ - see front matter q 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2004.10.092 Journal of Molecular Structure: THEOCHEM 723 (2005) 205–209 www.elsevier.com/locate/theochem * Corresponding author. Tel.: C91 512 2598544; fax: C91 512 2590007. E-mail address: arpitayadav@yahoo.co.in (A. Yadav).