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Binding analysis of compounds C1-7 and Ca v 2.2. C1-7 are shown in dark green, dark pink, dark sky blue, chartreuse, orange, dark magenta and firebrick colors in circles I-VII, respectively. The channel interacting residues are shown in grey wires and labeled in black color. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Source publication
Chronic neuropathic pain is the most complex and challenging clinical problem of a population that sets a major physical and economic burden at the global level. Ca2+-permeable channels functionally orchestrate the processing of pain signals. Among them, N-type voltage-gated calcium channels (VGCC) hold prominent contribution in the pain signal tra...
Contexts in source publication
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... These non-peptide conotoxin mimetics mimic the scaffolds of xconotoxin MVIIA, CVID and GVIA [62]. In total, out of 30 docked compounds ( Fig. S1; Table S1), 7 [40][41][42][43][44] were selected on the basis of their binding pattern at the pore region of Ca v 2.2 shared by S5 and S6 helices along with P-loop of each domain (Fig. 4, S2). These compounds contain dendritic, benzothiazole or anthranilamide scaffolds, attached with Y, L/K and R residues (Fig. 3, Table S2). The IC 50 values of 7 selected compounds against Ca v 2.2 are listed in Table S2. Compound C1 exhibits a dendritic scaffold. C2-4 contain benzothiazole, C5-6 have anthranilamide scaffold, whereas ...
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... C1 interacted with the residues of pore and S6 segments of Ca v 2.2. It exhibited favorable associations with 3 of the selectivity filter (SF) ring residues (Glu314, Glu663 and Glu1365) (Fig. 4I). Compounds C2 and C3 binding was prompted through hydrophobic association with residues of D I (pore), D III (S5, pore and S6) and D IV (pore and S6). Ala1652, Thr1653, Ser1696 residues of Ca v 2.2 were involved in hydrogen bonding with both compounds ( Fig. 4II, 4III). C4 exhibited association with D III (S5, pore and S6) and D IV ...
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... with 3 of the selectivity filter (SF) ring residues (Glu314, Glu663 and Glu1365) (Fig. 4I). Compounds C2 and C3 binding was prompted through hydrophobic association with residues of D I (pore), D III (S5, pore and S6) and D IV (pore and S6). Ala1652, Thr1653, Ser1696 residues of Ca v 2.2 were involved in hydrogen bonding with both compounds ( Fig. 4II, 4III). C4 exhibited association with D III (S5, pore and S6) and D IV (pore and S6), while a single hydrogen bond was observed with O-atom of Thr1653 residue (Fig. 4IV). Contrary to C2-C4, compounds C5-C6 showed interactions with the residues of D I (S5, pore and S6) and D II (S6). Moreover, a single H-bond was observed via Asn697 and ...
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... with residues of D I (pore), D III (S5, pore and S6) and D IV (pore and S6). Ala1652, Thr1653, Ser1696 residues of Ca v 2.2 were involved in hydrogen bonding with both compounds ( Fig. 4II, 4III). C4 exhibited association with D III (S5, pore and S6) and D IV (pore and S6), while a single hydrogen bond was observed with O-atom of Thr1653 residue (Fig. 4IV). Contrary to C2-C4, compounds C5-C6 showed interactions with the residues of D I (S5, pore and S6) and D II (S6). Moreover, a single H-bond was observed via Asn697 and Met313 residues, respectively (Fig. 4V, 4VI). Compound C7 exhibited a favorable number of hydrophobic associations with the residues of D I (S5, pore and S6), D II ...
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... association with D III (S5, pore and S6) and D IV (pore and S6), while a single hydrogen bond was observed with O-atom of Thr1653 residue (Fig. 4IV). Contrary to C2-C4, compounds C5-C6 showed interactions with the residues of D I (S5, pore and S6) and D II (S6). Moreover, a single H-bond was observed via Asn697 and Met313 residues, respectively (Fig. 4V, 4VI). Compound C7 exhibited a favorable number of hydrophobic associations with the residues of D I (S5, pore and S6), D II (S6), D III (pore) and D IV (pore). Furthermore, Met347, Asn697, Thr1653 and Thr1363 residues exhibited hydrogen bonding (Fig. 4VII). The schematic binding details are indicated in Fig. S2. These findings illustrate ...
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... II (S6). Moreover, a single H-bond was observed via Asn697 and Met313 residues, respectively (Fig. 4V, 4VI). Compound C7 exhibited a favorable number of hydrophobic associations with the residues of D I (S5, pore and S6), D II (S6), D III (pore) and D IV (pore). Furthermore, Met347, Asn697, Thr1653 and Thr1363 residues exhibited hydrogen bonding (Fig. 4VII). The schematic binding details are indicated in Fig. S2. These findings illustrate that only compound C1 exhibited bonding with three residues (E314, E663, and E1365) of the Ca 2+ ion SF ring, therefore, compound C1 may be a good choice for MD simulation ...
Citations
... In silico studies were performed as previously described (Shah and Rashid, 2020). Briefly, the 3-dimensional structures of cyclooxygenase (COX2) PDB ID: IPXX, interleukin (IL-1β) PDB ID: 2MIB, PDB ID: 2TNF for TNF-α, PDB ID: 3TTI for JNK, PDB ID: ILE5 for nuclear factor-kB (NFκB), PDB ID: 1DVE for HO-1, and PDB ID: 2LZ1 for Nrf2 were downloaded from the RCSB protein data bank in Discovery Studio (DSV). ...
Acetaminophen (N-acetyl p-aminophenol or APAP) is used worldwide for its antipyretic and anti-inflammatory potential. However, APAP overdose sometimes causes severe liver damage. In this study, we elucidated the protective effects of carveol in liver injury, using molecular and in silico approaches. Male BALB/c mice were divided into two experimental cohorts, to identify the best dose and to further assess the role of carveol in the nuclear factor E2-related factor; nuclear factor erythroid 2; p45-related factor 2 (Nrf2) pathway. The results demonstrated that carveol significantly modulated the detrimental effects of APAP by boosting endogenous antioxidant mechanisms, such as nuclear translocation of Nrf2 gene, a master regulator of the downstream antioxidant machinery. Furthermore, an inhibitor of Nrf2, called all-trans retinoic acid (ATRA), was used, which exaggerated APAP toxicity, in addition to abrogating the protective effects of carveol; this effect was accompanied by overexpression of inflammatory mediators and liver = 2ltoxicity biomarkers. To further support our notion, we performed virtual docking of carveol with Nrf2-keap1 target, and the resultant drug-protein interactions validated the in vivo findings. Together, our findings suggest that carveol could activate the endogenous master antioxidant Nrf2, which further regulates the expression of downstream antioxidants, eventually ameliorating the APAP-induced inflammation and oxidative stress.
Calcium (Ca ²⁺ ) signaling plays an important role in the regulation of many cellular functions. Ca ²⁺ -binding protein calmodulin (CaM) serves as a primary effector of calcium function. Ca ²⁺ /CaM binds to the death-associated protein kinase 1 (DAPK1) to regulate intracellular signaling pathways. However, the mechanism underlying the influence of Ca ²⁺ on the conformational dynamics of the DAPK1−CaM interactions is still unclear. Here, we performed large-scale molecular dynamics (MD) simulations of the DAPK1−CaM complex in the Ca ²⁺ -bound and-unbound states to reveal the importance of Ca ²⁺ . MD simulations revealed that removal of Ca ²⁺ increased the anti-correlated inter-domain motions between DAPK1 and CaM, which weakened the DAPK1−CaM interactions. Binding free energy calculations validated the decreased DAPK1−CaM interactions in the Ca ²⁺ -unbound state. Structural analysis further revealed that Ca ²⁺ removal caused the significant conformational changes at the DAPK1−CaM interface, especially the helices α1, α2, α4, α6, and α7 from the CaM and the basic loop and the phosphate-binding loop from the DAPK1. These results may be useful to understand the biological role of Ca ²⁺ in physiological processes.
Objective:
The study investigated the effect of newly synthesized benzimidazole derivatives against ethanol-induced neurodegeneration. According to evidence, ethanol consumption may cause a severe insult to the central nervous system (CNS), resulting in mental retardation, neuronal degeneration, and oxidative stress. Targeting neuroinflammation and oxidative stress may be a useful strategy for preventing ethanol-induced neurodegeneration.
Methodology:
Firstly, the newly synthesized compounds were subjected to molecular simulation and docking in order to predict ligand binding status. Later, for in vivo observations, adult male Sprague Dawley rats were used for studying behavioral and oxidative stress markers. ELIZA kits were used to analyse tumour necrosis factor-alpha (TNF-), nuclear factor-B (NF-B), interleukin (IL-18), and pyrin domain-containing protein 3 (NLRP3) expression, while Western blotting was used to measure IL-1 and Caspase-1 expression.
Results:
Our findings suggested that altered levels of antioxidant enzymes were associated with elevated levels of TNF-α, NF-B, IL-1, IL-18, Caspase-1, and NLRP3 in the ethanol-treated group. Furthermore, ethanol also caused memory impairment in rats, as measured by behavioural tests. Pretreatment using selected benzimidazole significantly increased the combat of the brain against ethanol-induced oxidative stress. The neuroprotective effects of benzimidazole derivatives were promoted by their free radical scavenging activity, augmentation of endogenous antioxidant proteins (GST, GSH), and amelioration of lipid peroxide (LPO) and other pro-inflammatory mediators. Molecular docking and molecular simulation studies further supported our hypothesis that the synthetic compounds Ca and Cb had an excellent binding affinity with proper bond formation with their targets (TNF-α and NLRP3).
Conclusion:
It is revealed that these benzimidazole derivatives can reduce ethanol-induced neuronal toxicity by regulating the expression of cytokines, antioxidant enzymes, and the inflammatory cascade.
