Structure-based design of promising natural products to inhibit thymidylate kinase from Monkeypox virus and validation using free energy calculations

• Published in: Computers in biology and medicine 2023-05, Vol.158, p.106797-106797, Article 106797
• Main Authors: Khan, Abbas, Adil, Shoaib, Qudsia, Hafiza Ayesha, Waheed, Yasir, Alshabrmi, Fahad M., Wei, Dong-Qing
• Format: Article
• Language: English
• Subjects: Accuracy; Alzheimer's disease; Binding; Binding energy; Binding free energy; Bioactivity; Biological activity; Biological Products - pharmacology; Cell cycle; Chemical bonds; Disease control; DNA viruses; Drugs; Energy; Energy of dissociation; Epidemics; Free energy; Herbal medicine; HIV; Human immunodeficiency virus; Humans; Hydrogen bonding; Hydrogen bonds; Identification methods; Infections; Kinases; Males; Molecular screening; Molecular structure; Monkeypox; Monkeypox virus - genetics; Mpox; Mpox (monkeypox); Natural products; Pandemics; Pies; Proteins; Public health; Severe acute respiratory syndrome coronavirus 2; Sexually transmitted diseases; Simulation; Smallpox; STD; TMPK; Traditional Chinese medicine; Vaccines; Viruses
• ISSN: 0010-4825; 1879-0534
• DOI: 10.1016/j.compbiomed.2023.106797

Monkeypox (MPXV) is a globally growing public health concern with 80,328 active cases and 53 deaths have been reported. No specific vaccine or drug is available for the treatment of MPXV. Hence, the current study also employed structure-based drug designing, molecular simulation, and free energy calculation methods to identify potential hit molecules against the TMPK of MPXV, which is a replicatory protein that helps the virus to replicate its DNA and increase the number of DNAs in the host cell. The 3D structure of TMPK was modeled with AlphaFold and screening of multiple natural products libraries (4,71,470 compounds) identified TCM26463, TCM2079, and TCM29893 from traditional Chinese medicines database (TCM), SANC00240, SANC00984, and SANC00986 South African natural compounds database (SANCDB), NPC474409, NPC278434 and NPC158847 from NPASS (natural product activity and species source database) while CNP0404204, CNP0262936, and CNP0289137 were shortlisted from coconut database (collection of open natural products) as the best hits. These compounds interact with the key active site residues through hydrogen bonds, salt bridges, and pie-pie interactions. The structural dynamics and binding free energy results further revealed that these compounds possess stable dynamics with excellent binding free energy scores. Moreover, the dissociation constant (KD) and bioactivity analysis revealed stronger activity of these compounds exhibit stronger biological activity against MPXV and may inhibit it in in vitro conditions. All the results demonstrated that the designed novel compounds possess stronger inhibitory activity than the control complex (TPD-TMPK) from the vaccinia virus. The current study is the first to design small molecule inhibitors for the replication protein of MPXV which may help in controlling the current epidemic and also overcome the challenge of vaccine evasion. •Monkeypox (MPXV) is a globally growing public health concern.•The current study design novel inhibitors for thymidylate kinase of MPXV.•The shortlisted compounds exhibit excellent binding free energy scores.•Dissociation constant and bioactivity analysis further validated the compounds.•This is the first study to design inhibitors for TMPK of MPXV.