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, Eâin and Eâim and their difference IEâinm 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.
Highlights
IntroductionThe 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 binding of the drug to the receptor will initially depend upon the types of chemical bonds that can be established between the drug and its receptor
This specificity of nucleoside group of reverse transcriptase inhibitors (NNRTIs) for the HIV-1-RT is due to presence in HIV-1RT and not in other RTs or DNA polymerases, of a flexible highly hydrophobic pocket in which a nonsubstrate analogue can fit snugly[2,3,4]
Summary
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 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. NNRTIs have a comparatively higher binding affinity for the enzymesubstrate 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. The hydrophobic nature of the NNRTIs pocket provides relatively few possibilities for polar interaction and hydrogen bonding. We have studied various forces governing the drug-
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