Abstract
The global resurgence of the monkeypox virus (MPXV) poses a serious threat to public health, necessitating the development of potent antiviral compounds. This study explored the potential of MPXV H1 phosphatase inhibitors using a computational biology approach, leveraging traditional knowledge from Indian Materia Medica. An in-house library of approximately 50,000 natural compounds from Indian Materia Medica was screened using molecular docking techniques, identifying 12,800 compounds with significant binding affinities, including ten hit compounds selected for further analysis. The top three hit compounds exhibited binding affinities as low as - 8.2 kcal/mol, surpassing the positive controls, Antimycin A (- 6.1 kcal/mol) and Tecovirimat (- 7.0 kcal/mol). These compounds were further optimized using Density Functional Theory (DFT), showing their significant electronic properties and redocked with the target. Molecular dynamics (MD) simulation demonstrated the structural stability of lead 3 and target complex over 200 ns with - 96.02 ± 1.00 kJ/mol binding energy, significantly outperforming the control Antimycin A (- 23.59 ± 2.97 kJ/mol) and Tecovirimat (- 49.07 ± 1.46 kJ/mol). These findings suggest that Lead 3 containing Lawsonia inermis, traditionally used for medicinal purposes, could be a potential source of antiviral agents against MPXV. This study provides a strong basis for further experimental validation and the development of novel therapeutic interventions against MPXV.