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NS3-4A, a serine protease, is a primary target for drug development against Hepatitis C Virus (HCV). However, the effectiveness of potent next-generation protease inhibitors is limited by the emergence of mutations and resulting drug resistance. To address this, in this study a structure-based drug design approach is employed to screen a large library of 7320 natural compounds against both wild-type and mutant variants of NS3-4A protease. Telaprevir, a widely used protease inhibitor, was recruited as the control drug. The top 10 compounds with favorable binding affinities underwent drug-likeness evaluation. Based on ADMET studies, complexes of NP_024762 and NP_006776 were selected for molecular dynamic simulations. Principal component analysis (PCA) was employed to explore the conformational space and protein dynamics of the protein-ligand complex using a Free Energy Landscape (FEL) approach. The cosine values obtained from FEL analysis ranged from 0 to 1, and eigenvectors with cosine values below 0.2 were chosen for further analysis. To forecast binding free energies and evaluate energy contributions per residue, the MM-PBSA method was employed. The results highlighted the crucial role of amino acids in the catalytic domain for the binding of the protease with phytochemicals. Stable associations between the top compounds and the target protease were confirmed by the formation of hydrogen bonds in the binding pocket involving residues: His1057, Gly1137, Ser1139, and Ala1157. These findings suggest the potential of these compounds for further validation through biological evaluation.Communicated by Ramaswamy H. Sarma.

Background: Improving mental health literacy (MHL) can reduce stigma towards mental illness, decreasing delays in help-seeking for mental disorders such as psychosis. We aimed to develop and assess the impact of an interactive MHL intervention on stigma related mental health knowledge and behaviour (SRMHKB) among youth in two urban colleges in South India., Methods: Incorporating input from stakeholders (students, teachers, and mental health professionals), we developed a mental health literacy module to address SRMHKB. The module was delivered as an interactive session lasting 90 min. We recruited 600 (300 males; 300 females; mean age 19.6) participants from two city colleges in Chennai from Jan-Dec 2019 to test the MHL module. We assessed SRMHKB before the delivery of the MHL intervention, immediately after, and at 3 and 6 months after the intervention using the Mental Health Knowledge Schedule (MAKS) and Reported and Intended Behaviour Scale (RIBS). We used generalised estimating equations (GEE) to assess the impact of the intervention over time., Results: Compared to baseline, there was a statistically significant increase in stigma related knowledge and behaviour immediately after the intervention (coefficient=3.8; 95% CI: 3.5,4.1) and during the 3-month (coefficient=3.4; 95% CI: 3.0,3.7) and 6-month (coefficient=2.4; 95% CI: 2.0,2.7) follow-up., Conclusion: Preliminary findings suggest that a single 90-minute MHL interactive session could lead to improvements in SRMHKB among youth in India. Future research might utilise randomised controlled trials to corroborate findings, and explore how improvements can be sustained over the longer-term., Competing Interests: Declaration of Competing Interest The authors declare no potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)