A MOLECULAR MODELING STUDY OF NUCLEOSIDE ANALOGS AS POTENTIAL ANTI-AIDS DRUGS

Cyclic and acyclic thymidine analogues may act as anti-human immunodeficiency virus agents. Several structures have been optimized using molecular mechanics, and electronic properties calculated using the modified neglect of differential overlap method. Introduction of an unsaturated bond into the ribose ring leads to a large increase in strain energy, but the quantum mechanical heat of formation remains reasonable. Electrostatic potentials were calculated based on partial atomic charges, and compared with the potential around thymidine. It is found that a common region of positive potential exists in the C3' region for the active compounds, and on this basis the unsynthesized acyclic compounds studied here may be active. In azidothymidine (AZT) the extent of twist around the N1-C1' bond determines the presence or absence of this feature. A relationship is found to exist between the molecular mechanics energy and the EC50 activity data for the azido-substituted compounds.