In Silico Study of Alkaloid Compounds with Computational Approach for Selection of Drug Leads for COVID-19

Abstract

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virulent source of COVID-19 disease. As a result of the rapid transmission of the viral agent and deficiency of specific drugs against the virus, a worldwide pandemic ensued with a terrifying death toll. Thus there is tremendous urgency to discover substances for the development of specific COVID-19 drugs. With increasing public interest in natural products, this study aims to discover alkaloid compounds capable of inhibiting SARS-CoV-2 with the assistance of bioinformatics. In this work, 298 alkaloids with reported antiviral properties were identified, and their biological activities were validated with QSAR analysis using the Pass Online server until only 7 alkaloids remained. Molecular docking studies for these 7 alkaloids onto SARS-CoV-2 3CLpro, a protein involved in viral replication, were carried out with AutoDock Vina, followed by in silico visualization of the protein-alkaloid interaction with Ligplot+ program and prediction of ADME-Tox properties of the alkaloids using Toxtree program and SwissADME online server. Fangchinoline, phenanthroindolizidine, and polyalthenol are predicted to have strong binding affinity with SARS-CoV-2 3CLpro. Visualization of the molecular interactions between the ligand and protein target, however, showed that homonojirimycin formed the most hydrogen bonds with the protein binding site. Most of the alkaloids have little to no violation of Lipinski’s Rule of 5, easy to moderate synthetic accessibility, and good pharmacokinetic properties. Fangchinoline, phenanthroindolizidine, and polyalthenol exhibited high binding affinity values to SARS-CoV-2 3CLpro, with polyalthenol predicted to possess the strongest binding interactions to the active site of the protein. Polyalthenol and phenanthroindolizidine confer the most versatility in terms of bioavailability, however, supplementary observation of phenanthroindolizidine for the prospect of mutagenicity is required before it can be recommended for further drug development