Discovery of Potential Compounds Against SARS-CoV-2 Based on 3CLpro/RdRp Dual-target: An In silico Approach

Background The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future. Objective This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs. Methods Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out. Results After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability. Conclusion Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti-SARS-COV-2 drugs.