Determination of Novel SARS-CoV-2 Inhibitors by Combination of Machine Learning and Molecular Modeling Methods

Güner E., Özkan Ö., YALÇIN ÖZKAT G., Ölgen S.

Medicinal Chemistry, vol.20, no.2, pp.153-231, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 20 Issue: 2
  • Publication Date: 2024
  • Doi Number: 10.2174/0115734064265609231026063624
  • Journal Name: Medicinal Chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Biotechnology Research Abstracts, Chemical Abstracts Core, MEDLINE
  • Page Numbers: pp.153-231
  • Keywords: adme prediction, Deep learning, docking, in vitro test, molecular dynamic, Root Mean Square Deviation, SARS-CoV-2, similarity search
  • Istanbul Technical University Affiliated: Yes


Introduction: Within the scope of the project, this study aimed to find novel inhibitors by combining computational methods. In order to design inhibitors, it was aimed to produce molecules similar to the RdRp inhibitor drug Favipiravir by using the deep learning method. Methods: For this purpose, a Trained Neural Network (TNN) was used to produce 75 molecules similar to Favipiravir by using Simplified Molecular Input Line Entry System (SMILES) representations. The binding properties of molecules to Viral RNA-dependent RNA polymerase (RdRp) were studied by using molecular docking studies. To confirm the accuracy of this method, compounds were also tested against 3CL protease (3CLpro), which is another important enzyme for the progression of SARS-CoV-2. Compounds having better binding energies and RMSD values than favipiravir were searched with similarity analysis on the ChEMBL drug database in order to find similar structures with RdRp and 3CLpro inhibitory activities. Results: A similarity search found new 200 potential RdRp and 3CLpro inhibitors structurally similar to produced molecules, and these compounds were again evaluated for their receptor interactions with molecular docking studies. Compounds showed better interaction with RdRp protease than 3CLpro. This result presented that artificial intelligence correctly produced structures similar to favipiravir that act more specifically as RdRp inhibitors. In addition, Lipinski's rules were applied to the molecules that showed the best interaction with RdRp, and 7 compounds were determined to be potential drug candidates. Among these compounds, a Molecular Dynamic simulation study was applied for ChEMBL ID:1193133 to better understand the existence and duration of the compound in the receptor site. Conclusion: The results confirmed that the ChEMBL ID:1193133 compound showed good Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), hydrogen bonding, and remaining time in the active site; therefore, it was considered that it could be active against the virus. This compound was also tested for antiviral activity, and it was determined that it did not delay viral infection, although it was cytotoxic between 5mg/mL-1.25mg/mL concentrations. How-ever, if other compounds could be tested, it might provide a chance to obtain activity, and compounds should also be tested against the enzymes as well as the other types of viruses.