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| - 3D-Quantitative Structure−Activity Relationships of HEPT Derivatives as HIV-1Reverse Transcriptase Inhibitors, Based on Ab Initio Calculations
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| - Comparative molecular field analysis (CoMFA) has been applied to a large set of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues. The starting geometry of HEPT was obtained fromcrystallographic data of HEPT/HIV-1 reverse transcriptase (RT) complexes. The structures of 101 HEPTderivatives were considered and fully optimized by ab initio molecular orbital calculations at the HF/3-21Glevel. The best CoMFA model is satisfactory in both statistical significance and predictive ability. It showsexcellent, high predictive ability as r2cv = 0.858. The derived model indicates the importance of stericcontributions (64.4%) as well as electrostatic interactions for the HIV-1 RT inhibition. In addition, stericand electrostatic contour maps from this analysis agree well with the experimentally observed trend thatthere are steric interactions between the side chain of HEPT and an aromatic ring of Tyr181. It is concludedthat a moderately sized group at C5 enhances contact with Tyr181 enough to push it into a position whichrenders the protein nonfunctional, but a smaller group has insufficient steric requirements to do this and alarger group renders the ligand too large for the cavity. The mutation-induced resistance of reverse transcriptaseis explained by this analysis. The obtained results not only lead to a better understanding of structuralrequirements of this set of compounds for the inhibition but also enable the suggestions for new and morepotent drugs.
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