Disclosing pathogenic processes of monkeypox (MPOX) and drug repurposing through host-transcriptomics analysis.

Monkeypox (MPOX) virus infection outbreak in Africa in 2022 was initially considered a neglected tropical disease (NTD). Now it is recognized as a global health problem. The recent global spread has emphasized the need for increased attention to combat MPOX. Although there are some vaccines against MPOX, most people worldwide are still not vaccinated due to their unawareness or unavailability. However, so far, there is no approved drug against MPOX yet. Therefore, effective drugs against MPOX are also essential. This study attempted to disclose pathogenic processes and therapeutic strategies of MPOX based on MPOX-associated host key-genes (hKGs). At first, three transcriptomic profile datasets were analyzed, identifying 166 common host differentially expressed genes (hDEGs) between MPOX patients and control groups, comprising 75 upregulated and 91 downregulated hDEGs. Subsequently, six top-ranked host key genes (hKGs): ALB, HSP90AA1, CDH1, PTPRC, IGF1, and ABL1, were identified as potential MPOX-causing genes through protein-protein interaction (PPI) network analysis. Functional enrichment analysis of these hKGs revealed critical pathogenic processes of MPOX infection, including biological processes, molecular functions, cellular components, and KEGG pathways. Regulatory network analysis involving transcription factors and miRNAs provided further insights into disease mechanisms. Based on molecular docking analysis, five top-ranked drug molecules Tecovirimat, Beclabuvir, Maraviroc, Raltegravir, and Brincidofovir were identified as potential repurposable therapeutics against MPOX. ADME/T and drug-likeness evaluations confirmed favorable pharmacokinetic properties for these candidates. Additionally, 100 ns molecular dynamics (MD) simulations of the top three complexes (ALB-Tecovirimat, CDH1-Maraviroc, and PPARG-Beclabuvir) demonstrated strong binding stability, supported by RMSD, RMSF, and MM-GBSA results. Therefore, the results provided in this study might be potential resources for diagnosis and therapies of MPOX patients. However, the findings require experimental validation in wet lab for further confirmation.