Nobiletin as a Neuroprotectant against NMDA Receptors: An In Silico Approach

Abstract

Excitotoxicity is a type of neurodegenerative disorder. It caused by excessive glutamate receptor activation, which leads to neuronal malfunction and fatality. The N-methyl-D-aspartate (NMDA) receptors are found in glutamatergic neurons, and their excessive activation is primarily responsible for excitotoxicity. They are activated by both glutamate binding and postsynaptic depolarization, facilitating Ca2+ entry upon activation. Therefore, they are now widely acknowledged as being essential targets for excitotoxicity issues. Molecular docking and molecular dynamics (MD) simulation analyses have demonstrated that nobiletin efficiently targets the binding pocket of the NMDA receptor protein and exhibits stable dynamic behavior at the binding site. In this study, five potential neuroprotectants, nobiletin, silibinin, ononin, ginkgolide B, and epigallocatechin gallate (EGCG), were screened against the glutamate NMDA receptors in humans via computational methods. An in silico ADMET study was also performed, to predict the pharmacokinetics and toxicity profile for the expression of good drug-like behavior and a non-toxic nature. It was revealed that nobiletin fulfills the criteria for all of the drug-likeness rules (Veber, Lipinski, Ghose, Muegge, and Egan) and has neither PAINS nor structural alerts (Brenks). In conclusion, nobiletin demonstrated a possible promising neuroprotectant activities compared to other selected phytochemicals. Further, it can be evaluated in the laboratory for promising therapeutic approaches for in vitro and in vivo studies.

Molecular Modeling Study of a Receptor–Orthosteric Ligand–Allosteric Modulator Signaling Complex

“…In Figure 5b, glutamate and residues within the orthosteric binding pocket nearly overlapped, indicating an insignificant conformational change of the orthosteric binding pocket after PAM binds to NMDAR. Thr115, Arg120, Thr173, and Asp214 formed hydrogen bonds between glutamate and NMDAR, which is also consistent with the search results of Sadaf et al 32 For the NAM group, the situation is slightly different in that after the simulation, the position of glutamate has changed with a mild shift (Figure 6b), leading to the ligand−residue interaction free energy difference between with/without NAM structures. As glutamate is a small molecule, its flexibility in a comparatively big binding pocket is acceptable.…”

Virtual Screening and Biological Evaluation of Novel Low Molecular Weight Protein Tyrosine Phosphatase Inhibitor for the Treatment of Insulin Resistance

“…The compounds filtered by pharmacophore models were further filtered by the “Filter by Lipinski and Veber Rules” module in DS2019. 23 The parameter of molecular weight was altered to 700.…”

Inhibitory Potential of the Ocimum sanctum Phytochemicals on Bruton’s Tyrosine Kinase, a Well-Known Drug Target for Treatment of Chronic Lymphocytic Leukemia: An In Silico Investigation

“…The detailed results of ADME/pharmacokinetics prediction analysis of the six top-ranked phytochemicals of O. sanctum are shown in Supplementary Table S1. The Swiss-ADME analysis of the top-ranked phytochemicals of O. sanctum using the ESOL method [25] predicted all the six phytochemicals (Vicenin-2, Luteolin-7-O-glucuronide, Molludistin, Galuteolin, Vitexin, and rosmarinic acid) as soluble in water, whereas, the Ali method [26,27] predicted the three phytochemicals (Galuteolin, Luteolin-7-O-glucuronide, and rosmarinic acid,) as moderately soluble, and three phytochemicals (Molludistin, Vitexin, and Vicenin-2) as purely soluble in water (Table 2 and Supplementary Table S1). Moreover, on applying the Lipinski rule of 5, we found that, among the six phytochemicals, the physiochemical properties of two compounds (Molludistin and Rosmarinic acid) did not violate any criterion among the set criteria, whereas Vitexin violated only one criterion.…”