Drug repurposing for Mpox: Discovery of small molecules as potential inhibitors against DNA‐dependent RNA polymerase using molecular modeling approach
Open Access
- 22 March 2023
- journal article
- research article
- Published by Wiley in Journal of Cellular Biochemistry
- Vol. 124 (5), 701-715
- https://doi.org/10.1002/jcb.30397
Abstract
Mpox (formerly Monkeypox), a zoonotic illness caused by the Mpox virus, belongs to the Orthopoxvirus genus in the family Poxviridae. To design and develop effective antiviral therapeutics against DNA viruses, the DNA-dependent RNA polymerase (DdRp) of poxviruses has emerged as a promising drug target. In the present study, we modeled the three-dimensional (3D) structure of DdRp using a template-based homology approach. After modeling, virtual screening was performed to probe the molecular interactions between 1755 Food and Drug Administration-approved small molecule drugs (<= 500 molecular weight) and the DdRp of Mpox. Based on the binding affinity and molecular interaction patterns, five drugs, lumacaftor (-11.7 kcal/mol), conivaptan (-11.7 kcal/mol), betulinic acid (-11.6 kcal/mol), fluspirilene (-11.3 kcal/mol), and imatinib (-11.2 kcal/mol), have been ranked as the top drug compounds interacting with Mpox DdRp. Complexes of these shortlisted drugs with DdRp were further evaluated using state-of-the-art all-atoms molecular dynamics (MD) simulations on 200 nanoseconds followed by principal component analysis (PCA). MD simulations and PCA results revealed highly stable interactions of these small drugs with DdRp. After due validation in wet-lab using available in vitro and in vivo experiments, these repurposed drugs can be further utilized for the treatment of contagious Mpox virus. The outcome of this study may establish a solid foundation to screen repurposed and natural compounds as potential antiviral therapeutics against different highly pathogenic viruses.Keywords
Funding Information
- Dalhousie Medical Research Foundation
- Li Ka Shing Foundation
- Canadian Institutes of Health Research (OV2170357, SBC171495, MZ1187236)
This publication has 56 references indexed in Scilit:
- Open Babel: An open chemical toolboxJournal of Cheminformatics, 2011
- Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributionsJournal of Cheminformatics, 2009
- AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibilityJournal of Computational Chemistry, 2009
- Monkeypox virus and insights into its immunomodulatory proteinsImmunological Reviews, 2008
- DrugBank: a knowledgebase for drugs, drug actions and drug targetsNucleic Acids Research, 2007
- Evaluating protein structures determined by structural genomics consortiaProteins, 2007
- The SWISS-MODEL workspace: a web-based environment for protein structure homology modellingBioinformatics, 2005
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- The Protein Data BankNucleic Acids Research, 2000
- Gapped BLAST and PSI-BLAST: a new generation of protein database search programsNucleic Acids Research, 1997