A Mechanistic In-silico Approach for Design and Evaluation of Novel (1H-indol-3-yl) Acetic Acid Analogues as Dual-action Anti-retroviral and Anti-bacterial Agents: A Foresight into Rational Drug Design Strategies.

INTRODUCTION: The pressing need for effective HIV-1 Reverse Transcriptase (HIV-1 RT) inhibitors and for agents that suppress Glucosamine-6-Phosphate (GlcN6P) is a significant challenge in combating viral infections and related diseases. Indole acetic acid analogues have demonstrated remarkable versatility in modulating both anti-viral and GlcN6P pathways, but potential dual-action inhibitors remain unexplored. In this research, we have taken an interdisciplinary in-silico approach to develop and evaluate a set of novel indole analogues as potential anti-retroviral and GlcN6P agents. The ability of indole acetic analogues to exhibit dual-action antiretroviral and antibacterial efficacy through inhibition of viral replication at various stages and bacterial cell wall biosynthesis, attributed to the presence of an aryl carboxylic group that enhances the favorability of hydrophobic interactions, van der Waals interactions, and π-π stacking, has made them promising scaffolds in drug discovery. METHODS: To validate these findings, we determined the binding modalities of the 1m analogue with several key proteins involved in glucosamine metabolism and viral replication using in silico molecular docking evaluations comprising molecular dynamics simulations, binding free energy calculations (MM-GBSA), ADMET predictions, trajectory analysis, and DFT calculations. RESULTS: Molecular dynamics studies of the most potent analogue 1m were performed over 300 ns, yielding MM-GBSA values of -71.96 ± 5.29 kcal/mol and -67.45 ± 6.16 kcal/mol for HIV-1 RT (PDB: 1RT2) and Glucosamine-6-phosphate (PDB: 2VF5), respectively. We also subjected compound 1m to predictive ADMET analysis to determine its pharmacokinetic characteristics and potential safety profile. Our results, carried out in parallel, showed that compound 1m mediated favourable binding events, forming long-lasting, stable complexes, and exhibited high binding affinities for the target proteins, comparable to those of the standard drugs Efavirenz and Ciprofloxacin. DISCUSSION: The promising nature of compound 1m as a drug-like molecule was highlighted in anticipatory ADMET studies, supporting further evaluation as a potential dual-action inhibitor of glucosamine-6-phosphate synthase and an antiretroviral agent, given its favourable drug-like properties. To summarise, the strategy of calculations, including molecular docking, dynamic simulations, MM-GBSA calculations, predictive ADMET studies and DFT calculations, provides information about the design and assessment of potent indole analogues as dual-action anti-retroviral and GlcN6P agents. CONCLUSION: Our comprehensive in silico research, comprising molecular docking, molecular dynamics simulations following MM-GBSA analysis, predictive ADMET analysis, trajectory analysis, and DFT studies, revealed strong binding affinity to amino acids, several hydrogen-bond interactions, structural stability, and drug-likeness properties, making compound 1m a lead pharmacophore in potential dual-action anti-retroviral and glucosamine-6-phosphate drug discovery.