American Journal of Immunology 4 (3): 33-42, 2008 ISSN 1553-619X © 2008 Science Publications Corresponding Author: V.K. Sahu, Department of Chemistry, Maharani Lal Kunwari (PG) College, Balrampur, Uttar Pradesh, 271201, India Tel: +919335236117 33 Hydrophobic, Polar and Hydrogen Bonding Based Drug-Receptor Interaction of Tetrahydroimidazobenzodiazepinones V.K. Sahu, A.K.R. Khan, R.K. Singh and P.P. Singh Department of Chemistry, Maharani Lal Kunwari (PG) College, Balrampur, Uttar Pradesh, 271201, India Abstract: Anti-HIV drug discovery has been increasingly focusing on HIV-1-RT (reverse transcriptase) as a potential therapeutic target. Tetrahydroimidazobenzodiazepinone (TIBO) belongs to non-nucleoside group of reverse transcriptase inhibitors (NNRTIs). A computational chemistry study has been performed on a series of tetrahydroimidazo-benzodiazepinones as HIV-1-NNRT inhibitors. Problem statement: In order to search out new drug of desired activity from the lead compounds, there was need to know the interaction of drugs with their receptor i.e., type of force(s) that have predominant role. Approach: Log P and SASA have been used for measurement of hydrophobic interaction, energy of protonation for measurement of most favorable hydrogen bond acceptor site, bond length and bond strain for measurement of strength of hydrogen bond formed between drug and receptor, atomic charges, ionization potential, electronegativity, E ‡ n and E ‡ m and their difference ∆E ‡ nm for measurement of polar interaction. The 3D modeling and geometry optimization of the compounds and receptor amino acids have been done by semiempirical method with MOPAC2002 associated with CAChe software. Results: The study has shown that hydrophobic interaction is predominant and made major contribution, while hydrogen bonding and polar interactions help in proper orientation of the compound (or its functional groups) to make maximam interaction. Conclusion: In this study theoretical technique has been discussed by which new hypothetical HIV-1- NNRT inhibitors can be developed prior to their synthesis only by introducing effective hydrophobic substituents at specific sites. Key words: Tetrahydroimidazobenzodiazepinones, NNRTIs binding pocket, hydrophobicity, hydrogen bond and effective atomic softness INTRODUCTION The binding of the drug (compound) to the receptor will initially depend upon the types of chemical bonds (covalent bond, ionic bond, hydrogen bond and hydrophobic interactions) that can be established between the drug and its receptor. The overall strengths of these bonds will vary and will determine the degree of affinity between the drug and the receptor. The affinity of the compound for the receptor is dependent upon its proper three-dimensional characteristics such as: its size, stereochemical orientation of its functional groups and its physical and electrochemical properties. In this study we have chosen twenty-one tetrahydroimidazobenzodiazepinone (TIBO) derivatives for drug-receptor interaction. TIBO belongs to non- nucleoside group of reversetranscriptase inhibitors (NNRTIs). The NNRTIs interect non-competitively with an allosteric site of the reverse transcriptase enzyme and thus do not directly impair the function of the substrate binding site [1] . In fact, NNRTIs have a comparatively higher binding affinity for the enzyme- substrate complex than for the free enzyme itself. Their interaction with the enzyme leads to a conformational change in the enzyme, resulting in a decrease in the affinity of the active site for the substrate. However, NNRTIs are active against the RT of only HIV-1 and not of HIV-2 or any other retrovirus. This specificity of NNRTIs for the HIV-1-RT is due to presence in HIV-1- RT and not in other RTs or DNA polymerases, of a flexible highly hydrophobic pocket in which a non- substrate analogue can fit snugly [2-4] . The hydrophobic pocket in HIV-1-RT is formed by the hydrophobic residues (Y181, Y184, Y187 and Y188) of the Y181- Y188 region [5] . The hydrophobic nature of the NNRTIs pocket provides relatively few possibilities for polar interaction and hydrogen bonding. In this article, we have studied various forces governing the drug-