In-silico screening of anti-viral compounds against monkeypox virus Thymidylate kinase.

Abstract

The monkeypox disease is a global emergency without a cure yet realized and available medications are used only to treat symptoms. Wide screening, identification, and validation of potential small molecule non-peptidomimetic compounds that can curb the disease is critical. This research was therefore carried out mainly to identify and design potential monkeypox virus thymidylate kinase (TMPK) inhibitors using in-silico methods. The specific objectives were to identify the potential competitive inhibitors of monkeypox thymidylate kinase using Virtual screening and Structure-based De-novo Drug Design methods and to characterize as well as validate the best identified potent inhibitors of TMPK using Binding Energy, and ADMET studies approaches. This research targeted the monkeypox virus thymidylate kinase enzyme, a very crucial enzyme in viral DNA synthesis. Here, an overall number of 9 compounds were identified: CHEBI:15744, m129, NPC472860, g16mol7, NPC 49173, g3mol1, g14mol13, g1mol13, and g7mol17 through a Drug design funnel. First, Structure-Based De-novo drug design followed by structural-based drug design (virtual screening) of 36,983 compounds from CHEBI, FDA, Malaria pathogen box, and NPASS small molecule databases. The binding affinity was then determined using Auto Dock Vina and the best hits were selected and taken for ADMET screening using QikProp to check their pharmacokinetic profiles. 9 hits with the least number of QikProp Stars were considered the best compounds. The compounds represented by g*mol* were generated through de-novo drug design. CHEBI:15744 had the highest binding affinity of the 9 compounds, being -9.7 Kcal/mol with g7mol17 having the least (-8.0 Kcal/mol). The best ADME/T features were demonstrated by compounds g1mol13 and g3mol1, which had 0 violations to the resemblance to known medicines parameter (#stars) as predicted by QikProp. NPC49713 had the greatest violations (8), followed by NPC 472860 with 7 violations. Compounds with 9 violations and above were not considered. The findings of this study would help identify novel inhibitors against TMPK from a pool of large databases and de-novo drug design. Furthermore, the nine identified inhibitors could be developed as efficient drug candidates.