A Computational Study of Carbazole Alkaloids from Murraya koenigii as Potential SARS-CoV-2 Main Protease Inhibitors

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 (M pro ) 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 M pro . 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 M pro (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 M pro 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 M pro . 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 M pro catalytic activity. Supplementary Information The online version contains supplementary material available at 10.1007/s12010-022-04138-6.

Recent updates in click and computational chemistry for drug discovery and development

“…Moreover, a lead compound 8 of DDP4 inhibitor ( Maslov et al, 2022 ) and acetamide derivative 9 ( Zhou et al, 2022 ) as P2Y14R antagonist were considered as drug candidates for treating type 2 diabetes and gout, respectively. Additionally, potential SARS-CoV-2 main protease inhibitor 10 ( Dong et al, 2023 ) and carbazole alkaloids from Murraya koenigii ( Wadanambi et al, 2023 ) were identified as a promising drug candidates for inhibiting coronavirus infection. Surprisingly, it had been reported a computationally guided asymmetric total synthesis of resveratrol dimers, which possessed a wide range of biological activities such as antioxidant, anti-tumor and cardiovascular activities ( Nakajima et al, 2022 ), suggesting that computationally guided organic synthesis may be a powerful strategy to advance the chemistry of natural products ( Figure 2 ).…”

An Update of Carbazole Treatment Strategies for COVID-19 Infection

“…Several studies [5,9,17,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62] describing the important role of carbazole derivatives in the treatment of COVID-19 are included in this review, cf. Table 1.…”

“…In addition, numerous carbazole derivatives have also been found to be useful for Alzheimer's disease [69]. Several carbazoles were assessed by research groups for a SARS-CoV-2 virus study [5,45,53,54,[56][57][58][59][60]70]. Despite vaccination against COVID-19, there is an urgent priority to identify additional antiviral drugs due to immune loss due to new variants of SARS-CoV-2; computational approaches have made a big contribution to the identification of antivirals by lowering costs and time and by accelerating analyzes of target interactions with candidate drugs [45,71].…”

“…The overlapping polyproteins (pp1a and pp1ab) are cleaved, in an autoproteolytic way, by SARS-CoV-2 Mpro (SC2-Mpro), and mature non-structural proteins (11 proteins) necessary for viral replication and transcription are produced [72]. The lack of a Mpro-like human protease, such as its unique selective ability of cleavage site, makes it a major therapeutic target for the detection of anti-SARS-CoV-2 drugs [53,70]. Moreover, ACE2 is used as a therapeutic target to control the COVID-19 outbreak, as an ACE2mediated mechanism allows the virus to enter permissive cells.…”

“…These activities are mainly due to the presence of compounds with a carbazole structure in its leaves, roots, and bark [81,82]. For such evidence, Wadanambi et al in 2022 [53] evaluated the inhibitory potential of carbazole alkaloids from Murraya koenigii against Mpro by computational study. Using 3WL (5,6,7-trihydroxy-2-phenyl-4H-chromen-4-one) as a reference inhibitor, five carbazole alkaloids 3-7 (Figure 3 tensive patients with COVID-19 [48].…”