Unveiling novel drug-like molecules against VP39 methyltransferase enzyme of monkeypox virus

The rising prevalence of the monkeypox virus (MPXV) presents a significant health challenge, underscoring the urgent need for effective antiviral agents. This study focuses on the VP39 methyltransferase (VP39 MTase) enzyme of MPXV, recognized as an important therapeutic target. Through structure-based virtual screening of the FDA-approved ASINEX antiviral library against the VP39 MTase enzyme, three promising VP39 MTase inhibitors were identified, with Sinefungin serving as a control molecule. The identified compounds — BDC_23170445, BDB_26412461, and BDB_26419079 — exhibited binding affinities of −10.2 kcal/mol, −10 kcal/mol and −10 kcal/mol, respectively. The stability of these interactions was rigorously evaluated using comprehensive molecular dynamics (MD) simulation, principal component analysis (PCA), intermolecular hydrogen bonding, secondary structure analysis, binding free energy estimation, and entropy energy estimation. All identified compounds complied with the Lipinski rule of five, confirming their potential as viable drug candidates. Furthermore, MD simulation indicated that the VP39 MTase-BDC_23170445 complex exhibited excellent dynamic stability. The dynamic conformational shifts associated with the functional changes of these compounds on VP39 M were fully characterized via PCA. Compound BDB_26412461 showed a strong H-bonding interaction with LIG_284@N3 across 628 frames, with an average bond distance of 2.8464 Å. The MMPBSA/GBSA revealed the most favorable scores for BDC_23170445. This work lays the groundwork for future studies aimed at translating these findings into effective anti-MPXV treatments and positions these compounds as leading candidates in the ongoing therapeutic pursuit of therapies for MPXV.