Design, molecular docking and MD simulation of novel estradiol-pyrimidine analogues as potential inhibitors of Mpro and ACE2 for COVID-19

Abstract

Objectives: Estradiol has become a hot topic in the past few years due to its role in COVID-19. The research on it is started with higher prevalence of COVID-19 in males than in females. As Estradiol is synthesized in greater quantity in females than in males, it was suggested that it provides a protective effect against COVID-19. In recent years, various in silico and in vitro studies revealed the efficacy of estradiol in COVID-19. So, considering the importance of estradiol, this manuscript is focused on designing and exploration of novel estradiol derivatives as potential inhibitors of Mpro and ACE2 for COVID-19. Methods: We designed novel small molecule estradiol derivatives and carried out molecular docking to identify the binding affinity with the COVID proteins, Mpro and ACE2. The behaviour and stability of the complex was checked through molecular dynamics simulations in 300 ns. Furthermore, binding energy was also calculated using the MMGBSA approach. ADMET revealed the druglikeness of the designed molecules. Results: Based on the binding energy obtained after molecular docking, the MD simulation against each protein Mpro and ACE2 was carried out for topmost compounds. Results indicated that the inhibitor inside the active site of the protein is stable as evident from RMSD and RMSF. The binding free energy i.e., MM-GBSA indicated that the compounds LIG323 (-30.85 kcal/mol) and LIG217 (-49.17 kcal/mol) are potential drug candidate against Mpro and ACE2, respectively. Evaluation of ADMET also justifies the druglikeness of the compounds. Conclusion: The outcome reveals that this study provides enough evidences for the consideration of LIG323 and LIG217 as potential inhibitors of Mpro and ACE2, respectively for treatment of COVID-19.

Keywords

• Molecular docking
• COVID-19
• SARS-CoV-2
• Molecular dynamics
• Estradiol
• Pyrimidine