Repurposing antiviral drugs against the human monkeypox virus DNA-dependent RNA polymerase; in silico perspective

We read with great interest the paper that was recently published in this journal by Orvis et al.1Eva O. Anabel N. Oskar A. Ana V. Ana M.G. Sara M. et al.Monkeypox outbreak in Madrid (Spain): clinical and virological aspects.J Infect. 2022; https://doi.org/10.1016/J.JINF.2022.07.005Abstract Full Text Full Text PDF Google Scholar regarding the emerging outbreak of human monkeypox in Madrid, Spain. According to the Centers for Disease Control and Prevention surveillance, the virus is reported in 99 countries and territories, with 47,652 confirmed cases (until August 26, 2022). The DNA-dependent RNA polymerase (DdRp) of poxvirus is a promising drug target for developing new chemotherapeutic antiviral drugs against DNA viruses. In this study, the DdRp of the HMV is modeled using its vaccinia virus as a homolog. After that, we repurposed 29 antiviral drugs on the equilibrated model (after a 100 ns molecular dynamics simulation run). The results revealed The effectiveness of the two antiviral drugs (Norov-29 and bemnifosbuvir) in binding the HMV DdRp active site with a comparable binding affinity (-24.26 ±4.43 and -21.32 ±6.43 kcal/mol) with the positive control, guanosine triphosphate (GTP) (-21.03 ±7.55 kcal/mol). These results need further experimental validation but promising as it was previously tested clinically in other viruses and had good pharmacological profiles. This may also pave the way for finding new circulating HMV inhibitors. The model of HMV was built via SWISS-MODEL server2Jerome E. Diogo S.M. Tillack Andreas F. Stefano F. AutoDock Vina 1.2.0: new docking methods, expanded force field, and python bindings.J Chem Inf Model. 2021; 61: 3891-3898https://doi.org/10.1021/acs.jcim.1c00203Crossref PubMed Scopus (227) Google Scholar based on the solved structure of the Vaccinia virus elongation complex (PDB ID: 6RID). The predicted model has good quality as judged by MolProbity analysis.3Davis Ian W. Andrew L.F. Chen Vincent B. Block Jeremy N. Kapral Gary J. Xueyi W. et al.MolProbity: all-atom contacts and structure validation for proteins and nucleic acids.Nucleic Acids Res. 2007; 35: W375-W383https://doi.org/10.1093/nar/gkm216Crossref PubMed Scopus (3000) Google Scholar Only 0.4% of residues (five) have phi or psi angles in the generously allowed region and no outliers in the Ramachandran plot. In HMV, the active site (D415, D417, and D419) was predicted in the Rpo147 chain at a β-turn between two helices. The structure of the Apo DdRp was subjected to 100 ns molecular dynamics (MD) simulation4James A.M. Teemu M. Roland S. Szilárd P. Smith Jeremy C. Berk H. et al.GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers.SoftwareX. 2015; 1–2: 19-25https://doi.org/10.1016/j.softx.2015.06.001Abstract Full Text Full Text PDF Scopus (9218) Google Scholar run aiming to equilibrate the system and visit the available conformations of the protein during this time domain. The molecular docking of analogs was performed by AutoDock Vina.2Jerome E. Diogo S.M. Tillack Andreas F. Stefano F. AutoDock Vina 1.2.0: new docking methods, expanded force field, and python bindings.J Chem Inf Model. 2021; 61: 3891-3898https://doi.org/10.1021/acs.jcim.1c00203Crossref PubMed Scopus (227) Google Scholar All active site residues (Asp415, Asp417, and Asp419) were treated as flexible. The search box was centered at the metal ion of the active site, and the box dimensions were set to 30 × 30 × 30 Å. In addition, the exhaustiveness was increased to 256 to account for the high torsions of the ligands.5Xuan-Yu M. Hong-Xing Z. Mihaly M. Meng C. Molecular docking: a powerful approach for structure-based drug discovery.Curr Comput Aided Drug Des. 2012; 7: 146-157https://doi.org/10.2174/157340911795677602Crossref Scopus (1303) Google Scholar The other parameters were accepted in their default values. The average binding affinities of the nucleoside analogs against the active site of HMV DdRp ranged from −5.92 to −6.59 kcal/mol. The average scores of the top ten compounds (including the positive controls; ATP, CTP, GTP, and UTP) are depicted graphically in Fig. 1. As shown in Fig. 1; Valopicitabine, HCV-1, and Bemnifosbuvir are the best compounds with average binding affinity values of -6.58 ±0.01 kcal/mol. These three compounds show lower binding energies than the four positive controls. At the same time, HCV-2 and Norov-29 compounds show lower binding energies than ATP, GTP, and UTP (-6.51 ±0.01 kcal/mol). Finally, BMS-986094 shows lower binding energies than ATP and GTP (-6.48 ±0.08 kcal/mol). The detailed interactions established upon docking are listed in Table 1. The primary interaction type between the compounds and the DdRp is the formation of hydrogen bonds (at least six H-bonds). Additionally, all these drugs establish at least one salt bridge interaction with R380. The active site residues (D415, D417, and D419) are bolded in Table 1 and are involved in H-bond formation in all the formed complexes except for the Valopicitabine-DdRp complex. The interactions are graphically rendered in Fig. 1B, where the formed interactions are depicted by blue lines (H-bonds) and dashed yellow lines (salt bridges). Cyan sticks show the interacting residues of the DdRp, whereas the other sticks are the ligands.Table 1The established interactions upon docking the top six drugs and the physiological ribonucleotides (ATP, CTP, GTP, and UTP) against HMV DdRp after dynamics.Compound (PubChem ID)Hydrogen bondsHydrophobic interactionsOthersnumberResiduesnumberResiduesnumberResiduesValopicitabine (15940324)7R287, Q381, A414, F416, and E420--2R380 asalt bridge andHCV-1 (5276734)11R380, Q381, D415, G418, D419, E420, and E421--2R380 asalt bridge andBemnifosbuvir (122527275)13R380, P382, S383, D415, G418, D419, and E4211R3803R380 asalt bridge and,bπ-cations. Active site residues are in bold.CTP7R287, Q381, D415, E420, and W422--3R287 asalt bridge and and R380 asalt bridge andHCV-2 (11290467)10R380, Q381, D415, G418, D419, and E421--1R380 asalt bridge andNorov_29 (88571722)9Q381, D415, G418, D419, and E421--2R380 asalt bridge and,bπ-cations. Active site residues are in bold.UTP6R380, Q381, P382, D415, D419, and W422--3R380 asalt bridge andBMS-986094 (49862756)7P382, H385, D419, E420, W422, and R757--3R287 asalt bridge and, R380 asalt bridge andATP9R380, P382, S383, D415, D417, D419, E420, and E421--3R380 asalt bridge and,bπ-cations. Active site residues are in bold.GTP8R380, Q381, L384, H385, D415, W422, and R757--3R380 asalt bridge anda salt bridge andb π-cations. Active site residues are in bold. Open table in a new tab We performed another round of MD simulation for the best five hits (Valopicitabine, HCV-1, Bemnifosbuvir, HCV-2, and Norov-29) and the positive control GTP to study the protein dynamics upon ligand binding. We neglected the compounds BMS-986094 and Lumicitabine as their clinical trials were terminated for safety issues.6Tariq A. Philip Y. Jeffrey S. Pockros Paul J. Jacob L. Mitchell S. et al.Cardiac dysfunction associated with a nucleotide polymerase inhibitor for treatment of hepatitis C.Hepatology. 2015; 62: 409-416https://doi.org/10.1002/HEP.27488Crossref PubMed Google Scholar,7ClinicalTrials.gov. Study to evaluate the antiviral activity, clinical outcomes, safety, tolerability, and pharmacokinetics of orally administered lumicitabine regimens in adult participants hospitalized with respiratory syncytial virus - study results - ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/results/NCT02935673. Accessed September 10, 2022.Google Scholar Fig. 2 shows the calculated MM/GBSA of the top four complexes (HCV-1-DdRp, HCV-2-DdRp, Norov-29-DdRp, and bemnifosbuvir-DdRp) in addition to the GTP-DdRp complex. Norov-29 (sky blue) and bemnifosbuvir (red) are the best two compounds based on the MM/GBSA calculations in binding DdRp of HMV with values (-24.26 ±4.43 and -21.32 ±6.43 kcal/mol) near the positive control (GTP) (blue) (-21.03 ±7.55 kcal/mol). These two drugs may be potential anti-DdRp and are suggested further analyzed by in vitro and in vivo assays. Conclusively, we report the effectiveness of anti-norovirus (Norov-29) and the anti-HCV and flaviviruses (Bemnifosbuvir) against HMV. Based on our docking results, dynamics simulation, and calculated binding energies, we suggest these two drugs against the DdRp of HMV. This could help in fighting against the current outbreak that spreading worldwide during the last few months. Jameel M. Abduljalil: Software, Writing – original draft. Abdo A. Elfiky: Visualization, Supervision, Investigation, Writing – review & editing. We declare that there is no conflict of interest regarding this paper's work or publication. We are thankful to Bibliotheca Alexandrina for providing access to their High-Performance Computing facility.