Browsing by Author "Dankwa, B."
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin(MDPI, 2021) Kwofie, S.K.; Broni, E.; Asiedu, S.O.; Kwarko, G.B.; Dankwa, B.; Enninful, K.S.; Tiburu, E.K.; Wilson, M.D.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.Item In silico screening of isocitrate lyase for novel anti-buruli ulcer natural products originating from Africa(Molecules, 2018-06) Kwofie, S.K.; Dankwa, B.; Odame, E.A.; Agamah, F.E.; Doe, L.P.A.; Teye, J.; Agyapong, O.; Miller, W.A.; Mosi, L.; Wilson, M.D.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. © 2018 by the authors.Item Molecular Docking and Dynamics Simulation Studies Predict Munc18b as a Target of Mycolactone: A Plausible Mechanism for Granule Exocytosis Impairment in Buruli Ulcer Pathogenesis(Toxins, 2019-03) Kwofie, S.K.; Dankwa, B.; Enninful, K.S.; Adobor, C.; Broni, E.; Ntiamoah, A.; Wilson, M.D.Ulcers due to infections with Mycobacterium ulcerans are characterized by complete lack of wound healing processes, painless, an underlying bed of host dead cells and undermined edges due to necrosis. Mycolactone, a macrolide produced by the mycobacterium, is believed to be the toxin responsible. Of interest and relevance is the knowledge that Buruli ulcer (BU) patients remember experiencing trauma previously at the site of the ulcers, suggesting an impairment of wound healing processes, the plausible effect due to the toxin. Wound healing processes involve activation of the blood platelets to release the contents of the dense granules mainly serotonin, calcium ions, and ADP/ATP by exocytosis into the bloodstream. The serotonin release results in attracting more platelets and mast cells to the wound site, with the mast cells also undergoing degranulation, releasing compounds into the bloodstream by exocytosis. Recent work has identified interference in the co-translational translocation of many secreted proteins via the endoplasmic reticulum and cell death involving Wiskott-Aldrich syndrome protein (WASP), Sec61, and angiotensin II receptors (AT2R). We hypothesized that mycolactone by being lipophilic, passively crosses cell membranes and binds to key proteins that are involved in exocytosis by platelets and mast cells, thus inhibiting the initiation of wound healing processes. Based on this, molecular docking studies were performed with mycolactone against key soluble n-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and regulators, namely Vesicle-associated membrane protein (VAMP8), Synaptosomal-associated protein (SNAP23, syntaxin 11, Munc13-4 (its isoform Munc13-1 was used), and Munc18b; and also against known mycolactone targets (Sec61, AT2R, and WASP). Munc18b was shown to be a plausible mycolactone target after the molecular docking studies with binding affinity of −8.5 kcal/mol. Structural studies and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding energy calculations of the mycolactone and Munc18b complex was done with 100 ns molecular dynamics simulations using GROMACS. Mycolactone binds strongly to Munc18b with an average binding energy of −247.571 ± 37.471 kJ/mol, and its presence elicits changes in the structural conformation of the protein. Analysis of the binding interactions also shows that mycolactone interacts with Arg405, which is an important residue of Munc18b, whose mutation could result in impaired granule exocytosis. These findings consolidate the possibility that Munc18b could be a target of mycolactone. The implication of the interaction can be experimentally evaluated to further understand its role in granule exocytosis impairment in Buruli ulcer.