Design of Novel Imidazole Derivatives as Potential Non-nucleoside Reverse Transcriptase Inhibitors Using Molecular Docking and Dynamics Strategies

Introduction: Human Immunodeficiency Virus (HIV) has become an epidemic causing Acquired Immunodeficiency Syndrome (AIDS). Highly active antiretroviral therapy (HAART) consists of Nucleoside Reverse Transcriptase Inhibitors (NRTIS), Nucleotide Reverse Transcriptase Inhibitors (NtRTIS), and Non- Nucleoside Reverse Transcriptase Inhibitors (NNRTIS) with HIV Protease Inhibitors (HIV PIs). However, the emergence of resistant strains of NNRTIS necessitates the search for better HIV-1-RT inhibitors. Methods: In this study, a series of novel imidazoles (SP01-SP30) was designed using molecular docking inside the non-nucleoside inhibitory binding pocket (NNIBP) of the HIV-1-RT (PDB ID-1RT2) using Glide v13.0.137, Autodock Vina, and FlexX v2.1.3. Prime MMGBSA was used to study the free energy of binding of the inhibitors with the target enzyme. Molecular dynamics simulation studies were carried out to discover the dynamic behavior of the protein as well as to unveil the role of the essential amino acids required for the better binding affinity of the inhibitor within the NNIBP of the enzyme. The QikProp software module of Schrodinger and online SwissADME were also used to evaluate the drug-likeliness of these compounds. Results: The imidazole derivative SP08 is predicted to be the most promising design compound that can be considered for further synthetic exploitations to obtain a molecule with the highest therapeutic index against HIV-1-RT. Conclusion: The results of the current study demonstrate the robustness of our in-silico drug design strategy that can be used for the discovery of novel HIV-1-RT inhibitors.