Title : Molecular Docking of Muntingia calabura fruit phenols against ESKAP serine - Lactamase enzymes
Abstract:
Antimicrobial resistance (AMR) has increased in prevalence globally. In particular, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa (ESKAP) are the most clinically-relevant pathogens due to their multidrug resistance. The ESKAP strains’ main resistance mechanism is the expression of β-lactamases that acylates and inactivates beta-lactam antibiotics. Muntingia calabura, locally known as aratiles, contains multiple phenolic phytochemical compounds that previously exhibited activity against Gram-positive and Gram-negative bacteria, but are untested for ESKAP inhibition. The study aimed to assess the pharmacological properties and the in silico inhibitory potential of nine phenol compounds isolated from the M. calabura fruit: guaiacol, p-methylguaiacol, o-cresol, carotol, 2,4-dimethylphenol, cedrol, eugenol, p-vinylguaiacol, and vanillin. All phenol ligands were docked against PBP5, PBP2a, TEM-52, Oxa-23, and Oxa-10 enzymes. The SwissADME test showed that all nine compounds are orally bioavailable under Lipinski’s Rule of Five. All phenols had no cardiotoxic and carcinogenic effects, although two ligands posed skin sensitization risks. In terms of Free Energies of Binding, cedrol was found to be the best-scoring ligand against PBP5 (-5.0), PBP2a (-5.9), TEM-52 (-6.5), and Oxa-10 (-5.7), while o-cresol was determined as the best-scoring ligand against Oxa-23 (-6.5). Additionally, multiple phenols demonstrated hydrogen, alkyl, and pi-alkyl bonds with the enzymes’ active site pockets, causing competitive inhibition and counteracting the serine acylation process in β-lactamases. This inhibitory mechanism has the potential to reduce rates of antibiotic breakdown. All ligands have the potential to act as competitive β-lactamase enzyme inhibitors, with cedrol and o-cresol emerging as the top compounds for future drug development, which make them viable candidates for antibiotic additives. Further research is necessary to determine the applicability of these observed effects of M. calabura fruit phenols in vitro.
Audience Takeaway:
- The audience can learn the in silico (computer-based) approach on how to algorithmically determine bioavailability properties of plant phytochemicals. Specifically, they will be familiar on the use of the Lipinski test and the BOILED Egg model to identify whether the plant compounds can be orally ingested and can permeate organs and blood-brain barriers.
- From the presentation, they can also learn how to identify toxicity risks of plant compounds through a Quantitative structure-activity relationship (QSAR) approach to plant molecular biology. This involves identifying the carcinogenic, cardiotoxic, and sensitization risks of a phytochemical.
- This study will also present an approach to expedite the natural/herbal drug discovery process by using molecular docking as a screening test for top-performing phytochemical compounds, so that researchers can limit the scope of the phytochemicals they will test before proceeding to in vitro lab tests.
- Overall, it can help the audience be familiar with computer-based methods for identifying bacterial enzyme inhibitors from natural compounds, which can help in two aspects of their research: (1) efficiency by using docking as a pre-screening process for compounds before in vitro experiments, and (2) mechanism of action which will allow them to identify and visualize phytochemical action at an intermolecular level (e.g. competitive and noncompetitive bonds to enzyme sites).
