A POSSIBLE MECHANISM OF MOLECULAR RECOGNITION FOR THE REVERSE-TRANSCRIPTASE OF HIV-1

The reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) is still a pivotal target for anti-AIDS therapy research. We examine in this paper ''classical'' RT inhibitors, the chain-terminating deoxynucleosides, as well as recently developed synthetic drugs. Comparison of their structures and electronic properties allowed us to speculate on a mechanism of inhibition Of RT with three different recognition schemes. The first one consists of in-plane H-bond interactions of the CONH binding site. The second one is related to out-of-plane interactions and seems to be favored by charge delocalization. It is also observed that a completely different chemical, BI-RG-587, has a binding site exhibiting remarkable similarity to those of the dideoxynucleosides. Also important is the observation that all drugs that we have examined present two nearly perpendicular planes, one of which is likely to be associated to hydrophobic interactions. This picture provides a simple basis for discussing the antiretroviral activity of the most potent inhibitors of HIV-1 RT. It also reveals that ddI is a poor inhibitor (relative to AZT) and ddU is inactive against HIV-1 replication for completely different reasons. The low-energy conformation of ddI gives rise to unfavorable van der Waals contacts. On the other hand, ddU cannot assume a conformation suitable for phosphorylation of its hydroxyl moiety. All these features are discussed in detail.