Browsing by Author "Miller, W.A."
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Item Development of a proteochemometric-based support vector machine model for predicting bioactive molecules of tubulin receptors(Springer, 2021) Agyapong, O.; Miller, W.A.; Wilson, M.D.; Kwofie, S.K.Microtubules are receiving enormous interest in drug discovery due to the important roles they play in cellular functions. Targeting tubulin polymerization presents an excellent opportunity for the development of anti-tubulin drugs. Drug resistance and high toxicity of currently used tubulin-binding agents have necessitated the pursuit of novel drug candidates with increased therapeutic potency. The design of novel drug candidates can be achieved using efficient computational techniques to support existing efforts. Proteochemometric (PCM) modeling is a computational technique that can be employed to elucidate the bioactivity relations between related targets and multiple ligands. We have developed a PCM-based Support Vector Machine (SVM) approach for predicting the bioactivity between tubulin receptors and small, drug-like molecules. The bioactivity datasets used for training the SVM algorithm were obtained from the Binding DB database. The SVM-based PCM model yielded a good overall predictive performance with an area under the curve (AUC) of 87%, Matthews correlation coefficient (MCC) of 72%, overall accuracy of 93%, and a classification error of 7%. The algorithm allows the prediction of the likelihood of new interactions based on confidence scores between the query datasets, comprising ligands in SMILES format and protein sequences of tubulin targets. The algorithm has been implemented as a web server known as TubPred, accessible via http://35.167.90.225:5000/.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 simulations studies of OmpATb identifies four potential novel natural product-derived anti-Mycobacterium tuberculosis compounds(Computers in Biology and Medicine, 2020-05-03) Kwofie, S.K.; Adobor, C.; Quansah, E.; Bentil, J.; Ampadu, M.; Miller, W.A.; Wilson, M.D.The outer membrane protein A (OmpATb) of Mycobacterium tuberculosis is a virulence factor that neutralizes the host pH to impede the uptake of hydrophilic antitubercular drugs. Identifying natural compounds with the potential to inhibit OmpATb could allow circumvention of the porin-like activities of OmpATb. Four potential leads comprising ZINC000003958185, ZINC000000157405, ZINC000000001392 and ZINC000034268676 were obtained by virtual screening of 6394 diverse natural products. Characterization of the binding interactions of the potential leads with OmpATb revealed nine critical residues comprising ARG86, LEU110, LEU113, LEU114, ALA115, PHE142, SER145, VAL146, and PHE151. Molecular dynamics simulations also revealed very stable protein-lead complexes. Most residues contributed lower binding energies to the overall molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energies of the interactions between the molecules and OmpATb protein. Induced Fit Docking (IFD) of the compounds regenerated poses of the molecular docking using AutoDock Vina. These molecules could be starting templates for designing inhibitors to bypass the pore mediating activities of OmpATb. Based on structural similarity, ZINC000034268676 was suggested as a potential scaffold for designing efflux pump inhibitors of the gate mediating activities of OmpATb and may enhance the uptake of hydrophilic drugs to reduce the duration time of tuberculosis treatment. Furthermore, structurally similar compounds available in the DrugBank database with a similarity threshold of 0.7 have been reported to exhibit antitubercular and anti-mycobacterial activities. These biomolecules can be further characterized experimentally to corroborate their antitubercular activity. Also, the skeletons of the molecules can be adopted as sub-structures for the design of future anti-mycobacterial drugs.Item Pharmacoinformatics-based identification of potential bioactive compounds against Ebola virus protein VP24(Computers in Biology and Medicine, 2019-08-24) Kwofie, S.K.; Broni, E.; Teye, J.; Quansah, E.; Issah, I.; Wilson, M.D.; Miller, W.A.; Tiburu, E.K.; Bonney, J.H.K.Background: The impact of Ebola virus disease (EVD) is devastating with concomitant high fatalities. Currently, various drugs and vaccines are at different stages of development, corroborating the need to identify new therapeutic molecules. The VP24 protein of the Ebola virus (EBOV) plays a key role in the pathology and replication of the EVD. The VP24 protein interferes with the host immune response to viral infections and promotes nucleocapsid formation, thus making it a viable drug target. This study sought to identify putative lead compounds from the African flora with potential to inhibit the activity of the EBOV VP24 protein using pharmacoinformatics and molecular docking. Methods: An integrated library of 7675 natural products originating from Africa obtained from the AfroDB and NANPDB databases, as well as known inhibitors were screened against VP24 (PDB ID: 4M0Q) utilising AutoDock Vina after energy minimization using GROMACS. The top 19 compounds were physicochemically and pharmacologically profiled using ADMET Predictor™, SwissADME and DataWarrior. The mechanisms of binding between the molecules and EBOV VP24 were characterised using LigPlot+. The performance of the molecular docking was evaluated by generating a receiver operating characteristic (ROC) by screening known inhibitors and decoys against EBOV VP24. The prediction of activity spectra for substances (PASS) and machine learning-based Open Bayesian models were used to predict the anti-viral and anti-Ebola activity of the molecules, respectively. Results: Four natural products, namely, ZINC000095486070, ZINC000003594643, ZINC000095486008 and sarcophine were found to be potential EBOV VP24-inhibitiory molecules. The molecular docking results showed that ZINC000095486070 had high binding affinity of −9.7 kcal/mol with EBOV VP24, which was greater than those of the known VP24-inhibitors used as standards in the study including Ouabain, Nilotinib, Clomiphene, Torimefene, Miglustat and BCX4430. The area under the curve of the generated ROC for evaluating the performance of the molecular docking was 0.77, which was considered acceptable. The predicted promising molecules were also validated using induced-fit docking with the receptor using Schrödinger and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The molecules had better binding mechanisms and were pharmacologically profiled to have plausible efficacies, negligible toxicity as well as suitable for designing anti-Ebola scaffolds. ZINC000095486008 and sarcophine (NANPDB135) were predicted to possess antiviral activity, while ZINC000095486070 and ZINC000003594643 to be anti-Ebola compounds. Conclusion: The identified compounds are potential inhibitors worthy of further development as EBOV biotherapeutic agents. The scaffolds of the compounds could also serve as building blocks for designing novel Ebola inhibitors.Item The Search for Putative Hits in Combating Leishmaniasis: The Contributions of Natural Products Over the Last Decade(Natural Products and Bioprospecting, 2021) Sakyi, P.O.; Devine, R.N.O.A.; Amewu, R.K.; Miller, W.A.; Kwofie, S.K.; Ismaila, E.Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/ EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.