In vitro and computational studies of the ß-lactamase inhibition and ß-lactam potentiating properties of plant secondary metabolites.

ß-lactam resistance in bacteria is primarily mediated through the production of ß-lactamases. Among the several strategies explored to mitigate the issue of ß-lactam resistance, the use of plant secondary metabolites in combination with existing ß-lactams seem promising. The present study aims to identify possible ß-lactam potentiating plant secondary metabolites following in vitro and in silico approaches. Among 180 extracts from selected 30 medicinal plants, acetone extract of Ficus religiosa (FRAE) bark recorded the least IC50 value of 3.9 mg/ml. Under in vitro conditions, FRAE potentiated the activity of ampicillin, which was evidenced by the significant reduction in IC50 values of ampicillin against multidrug resistant bacteria. Metabolic profiling following HR-LCMS analysis revealed the presence of diverse metabolites viz. flavonoids, alkaloids, terpenoids, etc. in FRAE. Further, ensemble docking of the FRAE metabolites against four Class A ß-lactamase (SHV1, TEM1, KPC2 and CTX-M-27) showed quercetin, taxifolin, myricetin, luteolin, and miquelianin as potential inhibitors with the least average binding energy. In molecular dynamic simulation studies, myricetin formed the most stable complex with SHV1 and KPC-2 while miquelianin with TEM1 and CTX-M-27. Further, all five metabolites interacted with amino acid residue Glu166 in Ω loop of ß-lactamase, interfering with the deacylation step, thereby disrupting the enzyme activity. The pharmacokinetics and ADMET profile indicate their drug-likeness and non-toxic nature, making them ideal ß-lactam potentiators. This study highlights the ability of metabolites present in FRAE to act as ß-lactamase inhibitors.Communicated by Ramaswamy H. Sarma.

Analyzing the potential of selected plant extracts and their structurally diverse secondary metabolites for α-glucosidase inhibitory activity: in vitro and in silico approach.

Inhibiting α-glucosidase activity is a therapeutic method to regulate post-prandial hyperglycemia in humans. Here, in-vitro and in-silico studies were used to find α-glucosidase inhibitory plant secondary metabolites (PSM). Among 408 solvent extracts from 70 plants tested for α-glucosidase inhibition, 174 had IC50 ≤ 3 mg/ml. α-glucosidase inhibitory PSM is found in several plant species and solvent extracts, indicating their diversity. Further, ensemble molecular docking and structural activity relationship analysis supported this hypothesis where the top 100 PSM with the least binding energy (BE) among the 539 PSM belonged to sesquiterpenoids (34%), catechols (11%), flavonoids (9%) and steroidal lactones (8%). Shortlisted 11 PSM were subjected to molecular dynamic simulation. Withanolide J recorded the least BE of -66.424 ± 22.333 kJ/mol, followed by Withacoagulin I (-64.665 ± 24.030 kJ/mol). When different simulation frames were analyzed, PSM of withanolide groups was stabilized in the narrow entrance of the active pocket forming H-bond with LYS156, TYR158, PHE159, PHE303 PRO312, LEU313, ARG315 and PHE134. Similarly, Hydroxytuberosone and 1, 8-Dihydroxy-3-carboxy-9, 10-anthraquinone (DHCA) formed H-bond with ASP307 located on the loop at the entrance of the active pocket. In the case of Neoliquiritin and Kaempferol-3-o-alpha-L-rhamnoside (KALR), glucose moiety interacted with the GLU277 and ASP215 (catalytic amino acid residues) through H-bonds. In addition, these 11 PSM were found to fulfil the criteria of drug-likeness as per Lipinski's rule of five and pharmacokinetic profile. The present study strengthens the library of α-glucosidase inhibitory plants and PSM, providing valuable information for Type-II Diabetes mellitus management.Communicated by Ramaswamy H. Sarma.

In silico studies evidenced the role of structurally diverse plant secondary metabolites in reducing SARS-CoV-2 pathogenesis.

Plants are endowed with a large pool of structurally diverse small molecules known as secondary metabolites. The present study aims to virtually screen these plant secondary metabolites (PSM) for their possible anti-SARS-CoV-2 properties targeting four proteins/ enzymes which govern viral pathogenesis. Results of molecular docking with 4,704 ligands against four target proteins, and data analysis revealed a unique pattern of structurally similar PSM interacting with the target proteins. Among the top-ranked PSM which recorded lower binding energy (BE), > 50% were triterpenoids which interacted strongly with viral spike protein-receptor binding domain, > 32% molecules which showed better interaction with the active site of human transmembrane serine protease were belongs to flavonoids and their glycosides, > 16% of flavonol glycosides and > 16% anthocyanidins recorded lower BE against active site of viral main protease and > 13% flavonol glycoside strongly interacted with active site of viral RNA-dependent RNA polymerase. The primary concern about these PSM is their bioavailability. However, several PSM recorded higher bioavailability score and found fulfilling most of the drug-likeness characters as per Lipinski's rule (Coagulin K, Kamalachalcone C, Ginkgetin, Isoginkgetin, 3,3'-Biplumbagin, Chrysophanein, Aromoline, etc.). Natural occurrence, bio-transformation, bioavailability of selected PSM and their interaction with the target site of selected proteins were discussed in detail. Present study provides a platform for researchers to explore the possible use of selected PSM to prevent/ cure the COVID-19 by subjecting them for thorough in vitro and in vivo evaluation for the capabilities to interfering with the process of viral host cell recognition, entry and replication.