Identification of some novel oxazine substituted 9-anilinoacridines as SARS-CoV-2 inhibitors for COVID-19 by molecular docking, free energy calculation and molecular dynamics studies

Abstract

Coronavirus disease (COVID-19), a life-threatening disease, is caused by SARS-CoV-2. The targeted therapeutics of small molecules helps the scientific community to fight against SARS-CoV-2. In this article, some oxazine substituted 9-anilinoacridines (A1–A48) was designed by docking, MM-GBSA and molecular dynamics (MD) simulation studies for their COVID-19 inhibitory activity. The docking of ligands A1–A48 against SARS-CoV-2 (PDB ID: 5R82) are performed by using Glide module, in silico ADMET screening by QikProp module, binding energy using Prime MM-GB/SA module, MD simulation by Desmond module and atomic charges were derived by Jaguar module of Schrodinger suit 2019-4. Compound A38 has the highest G-score (−7.83) when compared to all the standard compounds which are proposed for COVID-19 treatment such as ritonavir (−7.48), lopinavir (−6.94), nelfinavir (−5.93), hydroxychloroquine (−5.47) and mataquine (−5.37). Compounds A13, A23, A18, A7, A48, A46, A32, A20, A1 and A47 are significantly active against SARS-CoV-2 main protease when compared with hydroxychloroquine and mataquine. The residues GLN19, THR24, THR25, THR26, LEU27, HIE41, SER46, MET49, ASN119, ASN142, HIE164, MET165, ASP187, ARG188 and GLN189 of SARS-CoV-2 main protease play a crucial role in binding with ligands. The in silico ADMET properties of the molecules are within the recommended values. The binding free energy was calculated using PRIME MM-GB/SA studies. From the ligands A38, A13, A23, A18, A7, A48 and A46 with significant Glide scores may produce significant COVID-19 activity for further development. Compound A38 was subjected to MD simulation at 100 ns to study the dynamic behaviour of protein–ligand complex.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2
• COVID-19
• acridine
• oxazine
• docking studies
• in silico ADMET screening
• MM-GBSA
• molecular dynamics simulation

Acknowledgements

The authors express their sincere gratitude to JSS Academy of Higher Education & Research, Mysuru. The authors also thank the principal Dr. S. P. Dhanabal, JSS College of Pharmacy, Ooty, for the technical support.

Disclosure statement

No potential conflict of interest was reported by the authors.