De Novo Parallel Design, Synthesis, and Evaluation of Inhibitors Against the Reverse Transcriptase of Human Immunodeficiency Virus Type-1 and Drug-resistant Variants

We used molecular modeling to design de novo broad-range inhibitors against wild type and drug-resistant variants of the reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1). First, we screened for small fragments that would interact with each one of four RT structures (one wild type and three mutants). Then, these fragments were linked to build a scaffold molecule. Out of 27 different compounds that were synthesized, four inhibited the DNA polymerase activity of RT with IC₅₀ values below 10 µM. Compound 5f inhibited RT with an IC₅₀ value of about 3.5 µM, while inhibiting drug-resistant RT variants more efficiently than the clinically used drug, nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one). 5f also inhibited the RT ribonuclease H activity with an IC₅₀ of 20 µM and therefore, unlike nevirapine, targets both RT activities. Accordingly, 5f can serve as lead for developing novel inhibitors against RT that may be used to suppress HIV-1 growth.