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In order to understand molecular mechanism of antiviral drug resistance of HIV-1 reverse transcriptase (RT) as well as potent antiviral activity of 2,6-diaminopurine dioxolane (DAPD) [prodrug of (–)-β-D-dioxolane guanine (DXG)] against drug-resistant RTs, molecular modelling studies of three structurally distinct nucleoside RT inhibitor (NRTI)-triphosphates (TP) [zidovudine (AZT)-TP, lamivudine (3TC)-TP and DXG-TP] complexed with the wild-type (WT) and mutated RT were conducted. The computational analyses indicated that the antiviral activity and the calculated relative binding energy of the RT inhibitor triphosphates can be correlated, and the minimized structures gave information on the molecular mechanism of drug resistance conferred by mutations. The interactions between the NRTI-TP and adjacent amino acid residues (Lys65, Lys70, Arg72, Tyr115 and/or Gln151) played important roles in stabilizing the enzyme—inhibitor complex. Particularly, Arg72 was found to stabilize the dioxolane and oxathiolane sugar moiety through hydrogen bonding, which was responsible for favourable binding affinity of DXG-TP to AZT- as well as 3TC-resistant mutants. The conformational changes in these amino acid residues caused by mutation always affected the changes in the tertiary structures of enzyme-inhibitor complexes through either closing or opening the gap between the fingers and palm domains. The enzyme-inhibitor complexes with good binding affinity showed tight binding modes by closing the gap between the two domains, whereas weak inhibitors gave open and loose complexes.

Molecular Mechanism of DAPD/DXG against Zidovudine- and Lamivudine- Drug Resistant Mutants: A Molecular Modelling Approach