An Integrative Computational Approach for Design and Evaluation of Novel [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole Analogues as Dual-Action Anti-Retroviral and Anti-Bacterial Agents: Insights into Rational Drug Design Strategies

Abstract

The development of effective antiretroviral inhibitors (HIV-1 Reverse Transcriptase) and glucosamine-6-phosphate (GlcN6P) agents represent a significant challenge for combating viral infections and related diseases. In this study, we employed a multidisciplinary approach to design and evaluate a series of novel triazole analogs as potential candidates for anti-retroviral and glucosamine-6-phosphate agents. Using molecular docking, we explored the binding interactions between the RSA3 analog and the target proteins implicated in viral replication and glucosamine metabolism. Density functional theory (DFT) employing the 6-311++G(d,p) basis set was utilized for computational analysis, with a subsequent examination of the electronic parameters. The HOMO and LUMO orbitals as well as the molecular electrostatic potential map were investigated using DFT to characterize the reactivity of our molecule. Molecular dynamics simulations were performed to investigate the stability and dynamic behavior of the ligand-protein complex (RSA3) over time (300 ns). Furthermore, we employed MM-GBSA calculations of the compound RSA3 (molecular mechanics generalized band surface area) to estimate the binding free energies (−71.30 ± 7.26 kcal/mol and −67.86 ± 7.09 kcal/mol, respectively) and identified the most promising compounds with high affinity for the target proteins. Additionally, predictive absorption, distribution, metabolism, excretion and toxicity (ADMET) studies of compound RSA3 were conducted to assess its drug-like properties and potential safety profiles of the selected compound. Our results revealed that RSA3 has favorable binding interactions, is a stable complex and has significant binding affinity for target proteins. Moreover, predictive ADMET studies indicated that RSA3 possesses desirable drug-like properties, suggesting its potential for further investigation as an anti-retroviral agent and glucosamine-6-phosphate agent. Overall, this integrative computational approach combining molecular docking, DFT analysis, dynamics simulations, MM-GBSA and predictive ADMET studies provides valuable insights into the design and evaluation of novel triazole analogs with potential therapeutic applications, highlighting the importance of rational drug design strategies in the field of antiretroviral and glucosamine research.