The role of the microbiota–gut–brain (MGB) axis in mood regulation and depression treatment has gained attention in recent years, as evidenced by the growing number of animal and human studies that have reported the anti-depressive and associated gamma-aminobutyric acid-ergic (GABAergic) effects of probiotics developed from Lactobacillus rhamnosus bacterial strains in the gut microbiome. The depressive states attenuated by these probiotics in patients suffering from clinical depression also characterize the severe and relapse-inducing withdrawal phase of the addiction cycle, which has been found to arise from the intoxication-enabled hyperregulation of the hypothalamic–pituitary–adrenal (HPA) axis, the body’s major stress response system, and a corresponding attenuation of its main inhibitory system, the gamma-aminobutyric acid (GABA) signaling system. Therefore, the use of probiotics in the treatment of general cases of depression provides hope for a novel therapeutic approach to withdrawal depression remediation. This review discusses potential therapeutic avenues by which probiotic application of Lactobacillus rhamnosus strains can be used to restore the central GABAergic activity responsible for attenuating the depression-inducing HPA axis hyperactivity in addiction withdrawal. Also, information is provided on brain GABAergic signaling from other known GABA-producing strains of gut microbiota.

Background. Till date, there is no known antidote to cure diabetes mellitus despite the discovery and development of diverse pharmacotherapeutic agents many years ago. Technological advancement in natural product chemistry has led to the isolation of analogs of vitexin and isovitexin found in diverse bioresources. These compounds have been extensively studied to explore their pharmacological relevance in diabetes mellitus. Aim of the Study. The present review was to compile results from in vitro and in vivo studies performed with vitexin and isovitexin derivatives relating to diabetes mellitus and its complications. A systematic online literature query was executed to collect all relevant articles published up to March 2020. Results. In this piece, we have collected data and presented it in a one-stop document to support the multitargeted mechanistic actions of vitexin and isovitexin in controlling diabetes mellitus and its complications. Conclusion. Data collected hint that vitexin and isovitexin work by targeting diverse pathophysiological and metabolic pathways and molecular drug points involved in the clinical manifestations of diabetes mellitus. This is expected to provide a deeper understanding of its actions and also serve as a catapult for clinical trials and application research.

Buruli ulcer (BU) is caused by Mycobacterium ulcerans and is predominant in both tropical and subtropical regions. The neglected debilitating disease is characterized by chronic necrotizing skin lesions attributed to a mycolactone, which is a macrolide toxin secreted by M. ulcerans. The preferred treatment is surgical excision of the lesions followed by a prolonged combination antibiotic therapy using existing drugs such as rifampicin and streptomycin or clarithromycin. These antibiotics appear not to be adequately potent and efficacious against persistent and late stage ulcers. In addition, emerging drug resistance to treatment poses great challenges. There is a need to identify novel natural product-derived lead compounds, which are potent and efficacious for the treatment of Buruli ulcer. Natural products present a rich diversity of chemical compounds with proven activity against various infectious diseases, and therefore, are considered in this study. This study sought to computationally predict natural product-derived lead compounds with the potential to be developed further into potent drugs with better therapeutic efficacy than the existing anti-buruli ulcer compounds. The three-dimensional (3D) structure of Isocitrate lyase (ICL) of Mycobacterium ulcerans was generated using homology modeling and was further scrutinized with molecular dynamics simulations. A library consisting of 885 compounds retrieved from the AfroDb database was virtually screened against the validated ICL model using AutoDock Vina. AfroDb is a compendium of “drug-like” and structurally diverse 3D structures of natural products originating from different geographical regions in Africa. The molecular docking with the ICL model was validated by computing a Receiver Operating Characteristic (ROC) curve with a reasonably good Area Under the Curve (AUC) value of 0.89375. Twenty hit compounds, which docked firmly within the active site pocket of the ICL receptor, were assessed via in silico bioactivity and pharmacological profiling. The three compounds, which emerged as potential novel leads, comprise ZINC38143792 (Euscaphic acid), ZINC95485880, and ZINC95486305 with reasonable binding energies (high affinity) of −8.6, −8.6, and −8.8 kcal/mol, respectively. Euscaphic acid has been reported to show minimal inhibition against a drug-sensitive strain of M. tuberculosis. The other two leads were both predicted to possess dermatological activity while one was antibacterial. The leads have shown promising results pertaining to efficacy, toxicity, pharmacokinetic, and safety. These leads can be experimentally characterized to assess their anti-mycobacterial activity and their scaffolds may serve as rich skeletons for developing anti-buruli ulcer drugs.

Diabetes mellitus is a disorder characterized by higher levels of blood glucose due to impaired insulin mechanisms. Alpha glucosidase is a critical drug target implicated in the mechanisms of diabetes mellitus and its inhibition controls hyperglycemia. Since the existing standard synthetic drugs have therapeutic limitations, it is imperative to identify new potent inhibitors of natural product origin which may slow carbohydrate digestion and absorption via alpha glucosidase. Since plant extracts from Calotropis procera have been extensively used in the treatment of diabetes mellitus, the present study used molecular docking and dynamics simulation techniques to screen its constituents against the receptor alpha glucosidase. Taraxasterol, syriogenin, isorhamnetin-3-O-robinobioside and calotoxin were identified as potential novel lead compounds with plausible binding energies of −40.2, −35.1, −34.3 and −34.3 kJ/mol against alpha glucosidase, respectively. The residues Trp⁴⁸¹, Asp⁵¹⁸, Leu⁶⁷⁷, Leu⁶⁷⁸ and Leu⁶⁸⁰ were identified as critical for binding and the compounds were predicted as alpha glucosidase inhibitors. Structurally similar compounds with Tanimoto coefficients greater than 0.7 were reported experimentally to be inhibitors of alpha glucosidase or antidiabetic. The structures of the molecules may serve as templates for the design of novel inhibitors and warrant in vitro assaying to corroborate their antidiabetic potential.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2) has impacted negatively on public health and socioeconomic status, globally. Although, there are currently no specific drugs approved, several existing drugs are being repurposed, but their successful outcomes are not guaranteed. Therefore, the search for novel therapeutics remains a priority. We screened for inhibitors of the SARS-CoV-2 main protease and the receptor-binding domain of the spike protein from an integrated library of African natural products, compounds generated from machine learning studies and antiviral drugs using AutoDock Vina. The binding mechanisms between the compounds and the proteins were characterized using LigPlot+ and molecular dynamics simulations techniques. The biological activities of the hit compounds were also predicted using a Bayesian-based approach. Six potential bioactive molecules NANPDB2245, NANPDB2403, fusidic acid, ZINC000095486008, ZINC0000556656943 and ZINC001645993538 were identified, all of which had plausible binding mechanisms with both viral receptors. Molecular dynamics simulations, including molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations revealed stable protein-ligand complexes with all the compounds having acceptable free binding energies <−15 kJ/mol with each receptor. NANPDB2245, NANPDB2403 and ZINC000095486008 were predicted as antivirals; ZINC000095486008 as a membrane permeability inhibitor; NANPDB2403 as a cell adhesion inhibitor and RNA-directed RNA polymerase inhibitor; and NANPDB2245 as a membrane integrity antagonist. Therefore, they have the potential to inhibit viral entry and replication. These drug-like molecules were predicted to possess attractive pharmacological profiles with negligible toxicity. Novel critical residues identified for both targets could aid in a better understanding of the binding mechanisms and design of fragment-based de novo inhibitors. The compounds are proposed as worthy of further in vitro assaying and as scaffolds for the development of novel SARS-CoV-2 therapeutic molecules.