ABSTRACT
Ideally, an anti-HIV drug should (1) be highly active against wild-type and mutant HIV without allowing breakthrough; (2) have high oral bioavailability and long elimination half-life, allowing once-daily oral treatment at low doses; (3) have minimal adverse effects; and (4) be easy to synthesize and formulate. R278474, a new diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitor (NNRTI), appears to meet these criteria and to be suitable for high compliance oral treatment of HIV-1 infection. The discovery of R278474 was the result of a coordinated multidisciplinary effort involving medicinal chemists, virologists, crystallographers, molecular modelers, toxicologists, analytical chemists, pharmacists, and many others.
Subject(s)
Anti-HIV Agents , Nitriles , Pyrimidines , Administration, Oral , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Biological Availability , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Genome, Viral , HIV/genetics , HIV/isolation & purification , HIV Infections/drug therapy , HIV Infections/virology , Humans , Interdisciplinary Communication , Models, Molecular , Molecular Structure , Mutation , Nitriles/chemical synthesis , Nitriles/chemistry , Nitriles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrimidines/pharmacology , RilpivirineABSTRACT
There are several indications that a given compound or a set of related compounds can bind in different modes to a specific binding site of a protein. This is especially evident from X-ray crystallographic structures of ligand-protein complexes. The availability of multiple binding modes of a ligand in a binding site may present an advantage in drug design when simultaneously optimizing several criteria. In the case of the design of anti-HIV compounds we observed that the more active compounds that are also resilient against mutation of the non-nucleoside binding site of HIV1-reverse transcriptase make use of more binding modes than the less active and resilient compounds.