1 Sodium hydrogen sulphide (NaHS), a donor of hydrogen sulphide (H 2 S), produced dose-related relaxation of the rabbit isolated ileum (EC 50 , 76.4+7.9 mM) and rat vas deferens (EC 50 , 64.8+5.4 mM) and reduced ACh-mediated contraction of the guinea-pig isolated ileum. 2 NaHS also reduced the response of the guinea-pig (EC 50 , 80.0+5.7 mM) and rat (EC 50 , 108.2+11.2 mM) ileum preparations to electrical stimulation of the intramural nerves. In guinea-pig ileum this e ect was spontaneously reversible and mimicked by sodium nitroprusside (SNP, EC 50 , 2.1 mM). Combination of NaHS (20 mM) with SNP (0.5 mM) produced a greater than additive inhibition of the twitch response of the ileum to electrical stimulation. 3 The inhibitory e ect of NaHS on the ®eld-stimulated guinea-pig ileum was una ected by pretreatment with L-NAME (100 mM), indomethacin (10 mM), naloxone (1 mM) or glibenclamide (100 mM). Furthermore, NaHS (200 mM) did not a ect the contractile response of the ileum to KCl (10 to 60 mM). 4 Propargylglycine (PAG, 1 mM) and b-cyanoalanine (BCA, 1 mM) (inhibitors of cystathionine-glyase) but not aminooxyacetic acid (AOAA, 1 mM) (inhibitor of cystathionine-b-synthetase) caused a slowly developing increase in the contraction of the guinea-pig ileum to ®eld stimulation. This e ect was reversed by cysteine (1 mM). 5 These results show that NaHS relaxes gastrointestinal and urogenital smooth muscle and suggest that H 2 S is responsible for these e ects. The possibility that endogenous H 2 S, formed as a consequence of activation of intramural nerves, plays a part in controlling the contractility of the guinea-pig ileum is discussed.
The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial drugs has made the eradication of the disease difficult to achieve, thus warranting the search for new drug targets. We report here studies that used computational methods to identify inhibitors of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity from African flora. An integrated library of 7722 African natural product-derived compounds and known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two compounds NANPDB1406 and NANPDB2581 with binding affinities of −9.5 and −9.2 kcal/mol, respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs, including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 μM. NANPDB2581, NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415 and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding pocket of the LdCRK12. The molecules were pharmacologically profiled as druglike with inconsequential toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug design of novel leishmanicides but warrant further studies to evaluate their therapeutic 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.
Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.
The emergence of drug resistance against the known hookworm drugs namely albendazole and mebendazole and their reduced efficacies necessitate the need for new drugs. Chemically diverse natural products present plausible templates to augment hookworm drug discovery. The present work utilized pharmacoinformatics techniques to predict African natural compounds ZINC95486082, ZINC95486052 and euphohelionon as potential inhibitory molecules of the hookworm Necator americanus β tubulin gene. A library of 3390 compounds was screened against a homology-modelled structure of β tubulin. The docking results obtained from AutoDock Vina was validated with an acceptable area under the curve (AUC) of 0.714 computed from the receiver operating characteristic (ROC) curve. The three selected compounds had favourable binding affinities and were predicted to form no interactions with the resistance-associated mutations Phe167, Glu198 and Phe200. The compounds were predicted as anthelmintics using a Bayesian-based technique and were pharmacologically profiled to be druglike. Further molecular dynamics simulations and MM-PBSA calculations showed the compounds as promising anthelmintic drug leads. Novel critical residues comprising Leu246, Asn247 and Asn256 were also predicted for binding. Euphohelionon was selected as a template for the de novo fragment-based design of five compounds labelled A1, A2, A3, A4 and A5; with four of them having SAscore values below 6, denoting easy synthesis. All the five de novo molecules docked firmly in the binding pocket of the β tubulin with no binding interactions with the three known resistance mutation residues. Binding energies of −8.2, −7.6, −7.3, −7.2 and −6.8 kcal/mol were obtained for A1, A2, A3, A4 and A5, respectively. The identified compounds can serve as treasure troves from which future potent anthelmintics can be designed. The current study strives to assuage the hookworm disease burden, especially making available molecules with the potential to circumvent the chemoresistance.
We have previously shown computationally that Mycolactone (MLN), a toxin produced by Mycobacterium ulcerans, strongly binds to Munc18b and other proteins, presumably blocking degranulation and exocytosis of blood platelets and mast cells. We investigated the effect of MLN on endocytosis using similar approaches, and it bound strongly to the N-terminal of the clathrin protein and a novel SARS-CoV-2 fusion protein. Experimentally, we found 100% inhibition up to 60 nM and 84% average inhibition at 30 nM in SARS-CoV-2 live viral assays. MLN was also 10× more potent than remdesivir and molnupiravir. MLN’s toxicity against human alveolar cell line A549, immortalized human fetal renal cell line HEK293, and human hepatoma cell line Huh7.1 were 17.12%, 40.30%, and 36.25%, respectively. The cytotoxicity IC50 breakpoint ratio versus anti-SARS-CoV-2 activity was more than 65-fold. The IC50 values against the alpha, delta, and Omicron variants were all below 0.020 µM, and 134.6 nM of MLN had 100% inhibition in an entry and spread assays. MLN is eclectic in its actions through its binding to Sec61, AT2R, and the novel fusion protein, making it a good drug candidate for treating and preventing COVID-19 and other similarly transmitted enveloped viruses and pathogens.
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