Abstract
In the rural communities of sub-Saharan African (sSA) countries, malaria is being managed using phytocompounds. Artesunate is reported to inhibit Gephyrin E, a central, multi-domain scaffolding protein of inhibitory post-synapses. Neem plant and its metabolites like azadirachtin are being indicated for management of malaria by traditional healers. The present study was aimed to cheminformatically analyse the binding potential of artesunate and azadirachtin with various reactive moieties of Gephyrin E, to reduce malaria scourge. With molecular dynamics (MD), binding free energy estimation and binding affinity of artesunate and azadirachtin to Gephyrin E was done. GRIP docking was done to study the interactions of these test ligands with Gephyrin E (6FGC). MD simulation gave insights to structural changes upon binding of artesunate and azadirachtin in the ligand-binding pocket of Gephyrin E. Root mean square deviation (RMSD) and root mean square fluctuation (RMSF) were calculated. From the estimation, azadirachtin had a total binding energy of −36.97 kcal/mol; artesunate had a binding energy of −35.73 kcal/mol. The GRIP docking results provided a clearer evidence that artesunate has comparatively better binding affinity to Gephyrin E than azadirachtin, and the critical binding sites (in activity order) were cavity 3, 2, 8, and 6 for artesunate while for azadirachtin, it was cavity 6, 3, 8, and 2. The GRIP docking provided detailed interactions at the atomic levels, providing evidence; both compounds have chances to overcome the drug resistance problem, albeit higher for artesunate. Our findings added another piece of evidence that azadirachtin may be effective as an anti-malarial agent. The results herein may provide impetus for more studies into bioactive components of plant origin towards the effective management of malaria disease phenotype.
Highlights
There is an increase in the epidemiological burden of severe lifethreatening diseases on the human population across the globe
For a deep insight into the binding of Artesunate and Azadirachtin in the ligand-binding pocket of Gephyrin E, root mean square fluctuation (RMSF) was used to plot the residual fluctuations during the molecular dynamics (MD) simulation
In attempts to understand biochemical processes, the combination of both ligand and structure-function-based analysis for drug design approaches remains a promising tool for the discovery and development of new molecules with potential anti-malaria activities (Ojha and Ray, 2015)
Summary
There is an increase in the epidemiological burden of severe lifethreatening diseases on the human population across the globe. This has compelled researchers and clinicians to develop reliable therapeutic strategies against these diseases (Srivastava et al, 2019). Medicinal plants have been essential in health management since ancient times (Sofowora et al, 2013). Availability, affordability, relative safety, and efficacy of natural products have greatly contributed toward their success against some known severe diseases (Oniyangi and Cohall, 2018; Okoh, 2019, Srivastava et al, 2019), for instance, Camellia sinensis (L.) Kuntze and Erigeron breviscapus (Vaniot) Hand.-Mazz. Availability, affordability, relative safety, and efficacy of natural products have greatly contributed toward their success against some known severe diseases (Oniyangi and Cohall, 2018; Okoh, 2019, Srivastava et al, 2019), for instance, Camellia sinensis (L.) Kuntze and Erigeron breviscapus (Vaniot) Hand.-Mazz. as neuroprotective agents (López and Calvo, 2011), Ganoderma lucidum and Ganoderma sinense (species of Ganoderma) as antitumor agents (Lawal et al, 2019), etc
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