ABSTRACT
Despite COVID-19 vaccination, immune escape of new SARS-CoV-2 variants has created an urgent priority to identify additional antiviral drugs. Targeting main protease (Mpro) expressed by SARS-CoV-2 is a therapeutic strategy for drug development due to its prominent role in viral replication cycle. Leaves of Murraya koenigii are used in various traditional medicinal applications and this plant is known as a rich source of carbazole alkaloids. Thus, this computational study was designed to investigate the inhibitory potential of carbazole alkaloids from Murraya koenigii against Mpro. Molecular docking was initially used to determine the binding affinity and molecular interactions of carbazole alkaloids and the reference inhibitor (3WL) in the active site of SARS-CoV-2 Mpro (PDB ID: 6M2N).The top scoring compounds were further assessed for protein structure flexibility, physicochemical properties and drug-likeness, pharmacokinetic and toxicity (ADME/T) properties, antiviral activity, and pharmacophore modeling. Five carbazole alkaloids (koenigicine, mukonicine, o-methylmurrayamine A, koenine, and girinimbine) displayed a unique binding mechanism that shielded the catalytic dyad of Mpro with stronger binding affinities and molecular interactions than 3WL. Furthermore, the compounds with high affinity displayed favorable physicochemical and ADME/T properties that satisfied the criteria for oral bioavailability and druggability. The pharmacophore modeling study shows shared pharmacophoric features of those compounds for their biological interaction with Mpro. During the molecular dynamics simulation, the top docking complexes demonstrated precise stability except koenigicine. Therefore, mukonicine, o-methylmurrayamine A, koenine, and girinimbine may have the potential to restrict SARS-CoV-2 replication by inactivating the Mpro catalytic activity.