Structural virology has emerged as the foundation for the development of effective antiviral therapeutics. It is pivotal in providing crucial insights into the three-dimensional frame of viruses and viral proteins at atomic-level or near-atomic-level resolution. Structure-based assessment of viral components, including capsids, envelope proteins, replication machinery, and host interaction interfaces, is instrumental in unraveling the multiplex mechanisms of viral infection, replication, and pathogenesis. The structural elucidation of viral enzymes, including proteases, polymerases, and integrases, has been essential in combating viruses like HIV-1 and HIV-2, SARS-CoV-2, and influenza. Techniques including X-ray crystallography, Nuclear Magnetic Resonance spectroscopy, Cryo-electron Microscopy, and Cryo-electron Tomography have revolutionized the field of virology and significantly aided in the discovery of antiviral therapeutics. The ubiquity of chronic viral infections, along with the emergence and reemergence of new viral threats necessitate the development of novel antiviral strategies and agents, while the extensive structural diversity of viruses and their high mutation rates further underscore the critical need for structural analysis of viral proteins to aid antiviral development. This review highlights the significance of structure-based investigations for bridging the gap between structure and function, thus facilitating the development of effective antiviral therapeutics, vaccines, and antibodies for tackling emerging viral threats.

Structural virology has emerged as the foundation for the development of effective antiviral therapeutics. It is pivotal in providing crucial insights into the three-dimensional frame of viruses and viral proteins at atomic or near atomic-level resolution. Structure-based assessment of viral components, including capsids, envelope proteins, replication machinery, and host interaction interfaces, are instrumental in unravelling the multiplex mechanisms of viral infection, replication, and pathogenesis. The structural elucidation of viral enzymes, including proteases, polymerases, and integrases, has been essential in combating viruses like HIV, SARS-CoV-2, and influenza. Techniques including X-ray crystallography, Nuclear Magnetic Resonance spectroscopy, Cryo-electron Microscopy, and Cryo-electron Tomography have revolutionized the field of virology and significantly aided in the discovery of antiviral therapeutics. The ubiquity of chronic viral infections, along with the emergence and re-emergence of new viral threats necessitate the development of novel antiviral strategies and agents, while the extensive structural diversity of viruses and their high mutation rates further underscore the critical need for structural analysis of viral proteins to aid antiviral development. This review highlights the significance of structure-based investigations for bridging the gap between structure and function, thus facilitating the development of effective antiviral therapeutics, vaccines, and antibodies for tackling emerging viral threats.

Malaria represents a major global health concern, primarily due to the emergence of resistance against most currently available antimalarial drugs. This pressing issue necessitates the discovery of novel antimalarial agents to combat the escalating resistance. A cyclin-dependent kinase (CDK)-like protein, Pfmrk, found in Plasmodium falciparum, plays a crucial role in regulating cell proliferation and exhibits a 36.28% sequence homology with its human counterpart hCDK7. Pfmrk forms a complex with plasmodial cyclin (Pfcyc-1) and stimulates kinase activity. Pfcyc-1 from P. falciparum, with the highest sequence homology to human cyclin (cyclin H), binds and activates Pfmrk in a cyclin-dependent manner. This discovery provides the first indication that cyclin subunits may regulate both human and plasmodial CDKs in a similar fashion. In this study, we conducted molecular docking and simulation analysis to investigate the interaction between Pfmrk and a selection of the FDA-approved drugs retrieved from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap – were screened based on their binding energies, with the best-docked scores ranging between −8 kcal/mol and −12 kcal/mol. Further, evaluation through molecular dynamics simulations for 100 nanoseconds revealed that Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the amino acid residues located in the active site of Pfmrk. The results of the in silico investigation indicate that Lurasidone and Donovex exhibit antimalarial potential and could serve as promising Pfmrk inhibitors. Further, development of new drugs based on these findings warrants subsequent in vitro studies.

Objective: This study aims to investigate the antiviral properties of Cow-urine distillate (CUD) and identify potential compounds responsible for its antiviral activity, thereby exploring its therapeutic potential against Chikungunya virus (CHIKV). Methods: The study assessed the antiviral activity of crude CUD using in vitro cell-based assays performed in Vero cells. The characterization of CUD was performed using GC-MS to identify potential metabolites with antiviral properties. Computational docking studies elucidated these natural compounds' binding affinities and critical interactions with CHIKV nsP2 protease (nsP2Pro). The identified metabolites were evaluated for antiviral activity against CHIKV nsP2Pro via in silico, biochemical, and cell culture-based antiviral assays. The study further investigated the synergistic antiviral effect of CUD with natural compounds such as thymoquinone (TQ) and piperine (PIP) against CHIKV replication. Results: Treatment of CHIKV with CUD resulted in 90% reduction in plaques with 2% v/v of CUD (EC50 ~ 0.423%). Furthermore, four of the compounds identified from GC-MS demonstrated substantial inhibition at non-toxic doses, as validated by FRET assay and CHIKV plaque-reduction assay. The combination of 20 µM TQ + 20 µM PIP + 2% v/v GA was found to be very effective against CHIKV, which exhibited ~4 log or 99.99% virus reduction. Conclusion: The present findings establish the antiviral potential of CUD and provide an effective natural remedy against CHIKV infection.