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Session 65 Poster Session Antiretroviral Chemotherapy in Resource Limited Settings Session Time: 4:30-6:30 pm Room 4E-F

464-W. Molecular Mechanism of DAPD Anti-HIV Activity against AZT and 3TC Mutants-Molecular Modeling Studies of HIV-1 RT Y. H. Chong1, R. F. Schinazi2, and C. K. Chu*1 1Univ. of Georgia, Athens and 2Emory Univ. Sch. of Med., VA Med. Ctr., Decatur, GA Bakground: DAPD/DXG is known to maintain the anti-HIV-1 activity against AZT and 3TC resistant mutants in vitro and in vivo. In order to understand the molecular mechanism of DAPD/DXG, molecular modeling studies of DXGTP complexed with the wild-type (WT) HIV-1 RT and mutated RT (M41L/D67N/K70R/T215Y, M184V, K65R, L74V and K65R/Q151M) were conducted. Methods: Binding affinity of the examined structures toward HIV-1 RT was estimated by means of the differences (Erel) of relative binding energy between the inhibitor triphosphate (DXGTP)-RT complex and the corresponding natural substrate (dGTP)-RT complex in the energy-minimized states. Results: A good correlation was found between the antiviral activity and the calculated relative binding energy. In WT RT, Arg72 slides down to the binding site to stabilize dioxolane ring moiety of DXGTP by hydrogen bonding and this movement of Arg72 ends up with pulling palm domain into the fingers domain to form a tight complex. The formation of salt bridge among Asn67, Lys219, and Asp110 is responsible for the stabilization of the entire enzyme-inhibitor complex in AZT-resistant RT (M41L/D67N/K70R/T215Y). The mutation at Met184 induces a change in dioxolane sugar puckering mode from 3'-endo to 3'-exo, which enables the nearby Tyr115 to stabilize DXGTP by hydrogen bonding, and the mutated residue Val184 does not experience any steric hindrance with the bound analog (DXGTP). Taken together, stabilization of dioxolane moiety by Tyr115 as well as the lack of steric hindrance between DXGTP and Val184 provides a favorable binding of DXGTP to the 3TC-resistant RT (M184V). Conclusions: Generally, a good binding of DXGTP to the active site could be found when the dioxolane sugar moiety and/or the triphosphate part of DXGTP were stabilized by the interaction with nearby enzyme residues such as Arg72 and Tyr115, whose conformational changes close the gap between the fingers and palm domains resulting in a tight complex.

©2002 9th Conference on Retroviruses and Opportunistic Infections