In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

Kwofie, Samuel K.; Dankwa, Bismark; Odame, Emmanuel; Agamah, Francis E.; Doe, Lady P. A.; Teye, Joshua; Agyapong, Odame; Miller, Whelton A.; Mosi, Lydia; Wilson, Michael D.

doi:10.3390/molecules23071550

Cited by 30 publications

(24 citation statements)

References 97 publications

(127 reference statements)

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“…Therefore, HA maybe implicated in the apoptotic mechanisms. For a given compound activity, whenever the Pa > Pi, the predicted biological activity can be pursued experimentally (Jamkhande and Barde, 2014;Kwofie et al, 2018). Therefore, HA is an attractive antileishmanial candidate, which reinforces the results of the in vitro studies.…”

Section: Biological Activity Prediction For Hardwickiic Acidmentioning

confidence: 61%

Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus

et al. 2020

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Leishmania is a parasitic protozoon responsible for the neglected tropical disease Leishmaniasis. Approximately, 350 million people are susceptible and close to 70,000 death cases globally are reported annually. The lack of effective leishmanicides, the emergence of drug resistance and toxicity concerns necessitate the pursuit for effective antileishmanial drugs. Natural compounds serve as reservoirs for discovering new drugs due to their chemical diversity. Hardwickiic acid (HA) isolated from the stembark of Croton sylvaticus was evaluated for its leishmanicidal potential against Leishmania donovani and L. major promastigotes. The susceptibility of the promastigotes to HA was determined using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide/phenazine methosulfate colorimetric assay with Amphotericin B serving as positive control. HA showed a significant antileishmanial activity on L. donovani promastigotes with an IC 50 value of 31.57± 0.06 µM with respect to the control drug, amphotericin B with IC 50 of 3.35 ± 0.14 µM). The cytotoxic activity was observed to be CC 50 = 247.83 ± 6.32 µM against 29.99 ± 2.82 µM for curcumin, the control, resulting in a selectivity index of SI = 7.85. Molecular modeling, docking and dynamics simulations of selected drug targets corroborated the observed antileishmanial activity of HA. Novel insights into the mechanisms of binding were obtained for trypanothione reductase (TR), pteridine reductase 1 (PTR1), and glutamate cysteine ligase (GCL). The binding affinity of HA to the drug targets LmGCL, LmPTR1, LdTR, LmTR, LdGCL, and LdPTR1 were obtained as-8.0,-7.8,-7.6,-7.5,-7.4 and-7.1 kcal/mol, respectively. The role of Lys16, Ser111, and Arg17 as critical residues required for binding to LdPTR1 was reinforced. HA was predicted as a Caspase-3 stimulant and Caspase-8 stimulant, implying a possible role in apoptosis, which was shown experimentally that HA induced parasite death by loss of

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Section: Biological Activity Prediction For Hardwickiic Acidmentioning

confidence: 61%

Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus

et al. 2020

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“…Since ROC evaluates the overall performance of the docking method to distinguish between actives and inactive (overall enrichment) [37,38,39], early enrichment was evaluated using the BEDROC and EFs (Table 4). BEDROC values obtained were between 0.1 and 0.2, whilst EF scores averaged around 2.7 for 1% to 20% of the screened compounds.…”

Section: Resultsmentioning

confidence: 99%

Molecular Informatics Studies of the Iron-Dependent Regulator (ideR) Reveal Potential Novel Anti-Mycobacterium ulcerans Natural Product-Derived Compounds

et al. 2019

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Buruli ulcer is a neglected tropical disease caused by the bacterium Mycobacterium ulcerans. Its virulence is attributed to the dermo-necrotic polyketide toxin mycolactone, whose synthesis is regressed when its iron acquisition system regulated by the iron-dependent regulator (ideR) is deactivated. Interfering with the activation mechanism of ideR to inhibit the toxin’s synthesis could serve as a possible cure for Buruli ulcer. The three-dimensional structure of the ideR for Mycobacterium ulcerans was generated using homology modeling. A library of 832 African natural products (AfroDB), as well as five known anti-mycobacterial compounds were docked against the metal binding site of the ideR. The area under the curve (AUC) values greater than 0.7 were obtained for the computed Receiver Operating Characteristics (ROC) curves, validating the docking protocol. The identified top hits were pharmacologically profiled using Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMET) predictions and their binding mechanisms were characterized. Four compounds with ZINC IDs ZINC000018185774, ZINC000095485921, ZINC000014417338 and ZINC000005357841 emerged as leads with binding energies of −7.7 kcal/mol, −7.6 kcal/mol, −8.0 kcal/mol and −7.4 kcal/mol, respectively. Induced Fit Docking (IFD) was also performed to account for the protein’s flexibility upon ligand binding and to estimate the best plausible conformation of the complexes. Results obtained from the IFD were consistent with that of the molecular docking with the lead compounds forming interactions with known essential residues and some novel critical residues Thr14, Arg33 and Asp17. A hundred nanoseconds molecular dynamic simulations of the unbound ideR and its complexes with the respective lead compounds revealed changes in the ideR’s conformations induced by ZINC000018185774. Comparison of the lead compounds to reported potent inhibitors by docking them against the DNA-binding domain of the protein also showed the lead compounds to have very close binding affinities to those of the potent inhibitors. Interestingly, structurally similar compounds to ZINC000018185774 and ZINC000014417338, as well as analogues of ZINC000095485921, including quercetin are reported to possess anti-mycobacterial activity. Also, ZINC000005357841 was predicted to possess anti-inflammatory and anti-oxidative activities, which are relevant in Buruli ulcer and iron acquisition mechanisms, respectively. The leads are molecular templates which may serve as essential scaffolds for the design of future anti-mycobacterium ulcerans agents.

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“…For any given compound, PASS predicts the Pa and Pi, with both ranging between 0.000 and 1.000 for a predicted activity. When the Pa is greater than the Pi for a particular compound activity and Pa > 0.3, it is worth exploring the pharmacological activity [ 111 , 112 ]. PASS was used in previous studies to predict the antiviral activity of novel compounds, and the experimental results corroborated the PASS predictions [ 113 ].…”

Section: Methodsmentioning

confidence: 99%

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

et al. 2021

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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.

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In Silico Screening of Isocitrate Lyase for Novel Anti-Buruli Ulcer Natural Products Originating from Africa

Cited by 30 publications

References 97 publications

Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus

Leishmanicidal Potential of Hardwickiic Acid Isolated From Croton sylvaticus

Molecular Informatics Studies of the Iron-Dependent Regulator (ideR) Reveal Potential Novel Anti-Mycobacterium ulcerans Natural Product-Derived Compounds

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin

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