Molecular Docking, ADMET, DFT Studies, and Retrosynthesis Strategy of New Benzimidazolone Derivatives as HIV-1 Reverse Transcriptase (RT) Inhibitors

HIV-1, or Human Immunodeficiency Virus type 1, is a global pandemic that affects millions of individuals worldwide. As a multifunctional enzyme in this virus's life cycle, reverse transcriptase (RT) is a significant target for drugs discovery. RT inhibitors are primarily classified into two types: non-nucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs), though other classes, like nucleotide reverse transcriptase inhibitors (NtRTIs), also exist. Molecular docking and pharmacophore modeling approaches and DFT (Density Functional Theory) calculations are an important step in HIV-1 drug discovery. In the current study, we used in silico approaches to explore the binding modes of a novel series of benzimidazolone (1,3-dihydro-2H-benzimidazol-2-one) derivatives. Accordingly, the benzimidazolone compounds were tested against both wild-type and mutated forms of HIV-1 RT, including the K103N, Y181C, and the double mutant K103N/Y181C. The results from molecular docking allowed us to select two benzimidazolone compounds (L15 and L17) as promoting inhibitors with good binding affinity not only against the wild-type HIV-1 (L15: -11.5 Kcal/mol and L17: -11.4 Kcal/mol), but also against the mutants RT Y181C (L15: -11.2 Kcal/mol and L17: -10.1 Kcal/mol), K103N (L15: -11.5 Kcal/mol and L17: -11.6 Kcal/mol), and double mutant K103N/Y181C (L15: -11.1 Kcal/mol and L17: -9.9 Kcal/mol). Furthermore, the designed ligands are characterized by desirable pharmacokinetic properties based on ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity). At the end of this work, a retrosynthesis study of the drug candidates (L15 and L17) was carried out to simplify their synthesis.

Molecular Docking, ADMET, DFT Studies, and Retrosynthesis Strategy of New Benzimidazolone Derivatives as HIV-1 Reverse Transcriptase (RT) Inhibitors Keywords:

ADMET , Benzimidazol-2-one , DFT , Molecular docking , Drug design , Reverse Transcriptase