Ligand-protein interactions of plant-isolated (9z,12z)-octadeca-9,12-dienoic acid with Β-ketoacyl-Acp synthase (KasA) in potential anti-tubercular drug designing.

Mycobacterium tuberculosis remains one of the world's contributors to mortality. With the emergence of SARS-CoV-2 coinfections, patients with TB are predisposed to being more heavily weighed down by COVID-19 disease and its opportunistic coinfections. The severity of the disease coupled with drug resistance on the currently used drugs warrants for the search for alternative remedies from synthetic agents, semisynthetics and natural products that include plants. Africa is rich in plant diversity with a promise as sources of drug agents, one of which is Eichhornia crassipes. This work aimed at isolating a fatty acid and dock it to ß-ketoacyl-ACP synthase for possible anti-TB drug development prospects using computational tools. (9z,12z)-Octadeca-9,12-dienoic acid was isolated from Eichhornia crassipes for the first time using chromatographic techniques and identified using 1D and 2D NMR spectroscopic methods (1H NMR, COSY, HSQC, HMBC and 13C NMR). The compound was then docked to ß-ketoacyl-ACP synthase (KasA), an essential member of the b-ketoacyl synthases encoded in the M. tuberculosis genome in comparison with its co-crystallized ligand JSF-3285, also for the first time. (9z,12z)-Octadeca-9,12-dienoic acid interacted with only phenylalanine239 and proline201 while JSF-3285 interacted with proline201, glutamine120, alanine119, leucine116, glutamine199, histadine345, phenylalanine239, glycine240 and glycine200. (9z,12z)-Octadeca-9,12-dienoic acid had a ligand efficiency of 0.24, compared to the co-crystallized ligand's 0.36. The compound was too flexible and elongated with -4.72 KCalmol-1 binding energy. Despite some unfavourable physico-chemical properties, the compound still provides reliable interactions that only require logical structural modifications by the addition of polar regions amongst others to increase interactions and ligand efficiency, which can consequently stand to be a better potential drug lead. For the first time, plant-based (9z,12z)-Octadeca-9,12-dienoic acid isolated from Eichhornia crassipes was shown to interact fairly well with ß-ketoacyl-ACP synthase and proved to be a potential starting material from which anti-tubercular drugs can be designed.

Structural and In Silico Characterization of Small Molecules Isolated from Eichhornia crassipes.

Eichhornia crassipes has been reported to have various medicinal properties including anticancer activities. The plant was collected from the Shire river in Malawi, and two cytotoxic compounds, benzene-1,4-diol and nonanedioic acid, were isolated and characterized for the first time in the leaves and roots of the plant. 1H NMR, COSY, HSQC, HMBC, 13-C, and LCMS spectroscopic experimental techniques were used to identify the compounds in their pure forms. In silico experiments showed that both compounds do not have AMES toxicity and do not inhibit cytochrome P450 enzymes, but nonanedioic acid acts as a CYP2D6 substrate. This work showed that Eichhornia crassipes can be considered to have a role as a source of potential hits and leads to drug development that can be rationally optimized for drugs.

Momordica charantia L. lowers elevated glycaemia in type 2 diabetes mellitus patients: Systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Momordica charantia Linnaeus (Cucurbitaceae) has been extensively used traditionally as food and herbal medicine for type 2 diabetes mellitus in Asia, Brazil, and east Africa. In vitro and in vivo studies suggest its glycemic control potential; however, clinical studies produced conflicting results. AIM OF THE STUDY: To evaluate the efficacy of M. charantia preparations in lowering elevated plasma glucose level in prediabetes and type 2 diabetes mellitus patients. METHODS: Electronic search of the Cochrane library, PubMed®, CINAHL, and SCOPUS databases was done from 1st January 1960-30th April 2018 without language restriction. Two independent reviewers extracted data and assessed risk of bias of articles. Revman var. 5.3 software was used for data synthesis in meta-analysis. Heterogeneity was assessed using Chi-square and I2 tests. Treatment effect was estimated using mean difference at follow up in outcome measures between M. charantia preparations and placebo or oral hypoglycemic agents control group. The protocol of this study has a registration number PROSPERO CRD42018083653. RESULTS: Ten studies of type 2 diabetes mellitus (n = 1045) were included in the meta-analysis. They had 4-16 weeks follow up and overall moderate to high risk of bias. Compared to placebo, M. charantia monoherbal formulation significantly reduces FPG, PPG and HBA1c with mean difference of - 0.72 mmol/L, (95% CI: -1.33, -0.12), I2 = 14%, - 1.43 mmol/L, (95% CI: -2.18, -0.67), I2 = 0, - 0.26%, (95% CI: -0.49, -0.03), I2 = 0 respectively. M. charantia also lowered FPG in prediabetes (mean difference -0.31 mmol/L, n = 52); the evidence was downgraded to low quality because the study had unclear risk of bias and inadequate sample size. No serious adverse effects were reported. CONCLUSION: M. charantia adjunct preparations improved glycemic control in T2DM patients. However, this conclusion is based on low to very low quality evidences for the primary outcomes and sparse data for several safety outcomes, thus, warrant further research. Particularly needed are the researches that focus on standardizing M. charantia formulation and determine its efficacy and safety in clinical trials with adequate sample size, designed with random sequence generation, allocation concealment of intervention and blinding of both research personnel and participants.

Safety and efficacy of Momordica charantia Linnaeus in pre-diabetes and type 2 diabetes mellitus patients: a systematic review and meta-analysis protocol.

BACKGROUND: Momordica charantia Linnaeus (Cucurbitaceae) has been used traditionally as a nutritious food and as a herbal medicine for type 2 diabetes mellitus. However, human studies that investigated its glycemic control have generated inconsistent findings. Therefore, this systematic review and meta-analysis is aimed at evaluating the safety and efficacy of M. charantia L. preparations in human studies that have investigated its role in glycemic control. METHODS: This protocol has been prepared according to Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). The review will include randomized clinical trials and non-randomized clinical trials. The included studies will have assessed glycemic control of M. charantia preparations with placebo or standard oral anti-hyperglycemic agents in adult pre-diabetes and/or type 2 diabetes mellitus patients and have at least 4 weeks of follow-up. The primary outcomes of review are fasting blood glucose levels, glycosylated hemoglobin A1c, and post-prandial blood glucose level. Electronic database search for published literatures will be conducted without language restriction in EMBASE, MEDLINE/PubMed, the Cochrane Library, SCOPUS, Web of Sciences, and CINAHL databases. Search for gray literatures and references of the retrieved full-text articles will be conducted in Google, Google Scholar, OpenGrey, ProQuest dissertations & Theses, British Library EThos, and university digital library systems. Two independent reviewers will later evaluate full texts, extract data, and assess risk of bias of eligible articles. Publication biases will be assessed by testing asymmetry of funnel plot using Egger's or Begg's tests while heterogeneity will be assessed using Cochran Q test, P value, and I2. Revman software version 5.3 will be used for meta-analysis including subgroup and sensitivity analysis. DISCUSSION: This systematic review and meta-analysis will investigate both safety and efficacy of M. charantia preparations in type 2 diabetes mellitus. The review results will be published in a peer-reviewed journal. The results will bring better understanding of clinical outcomes in treatment of type 2 diabetes mellitus patients and highlight gaps for future research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018083653 .