Binding mechanism of inhibitors to p38α MAP kinase deciphered by using multiple replica Gaussian accelerated molecular dynamics and calculations of binding free energies

3区 · 工程技术

Article

作者: Sun, Haibo ; Chen, Jianzhong ; Pang, Laixue ; Wang, Wei ; Bao, Huayin

The p38α MAP Kinase has been an important target of drug design for treatment of inflammatory diseases and cancers. This work applies multiple replica Gaussian accelerated molecular dynamics (MR-GaMD) simulations and the molecular mechanics generalized Born surface area (MM-GBSA) method to probe the binding mechanism of inhibitors L51, R24 and 1AU to p38α. Dynamics analyses show that inhibitor bindings exert significant effect on conformational changes of the active helix α2 and the conserved DFG loop. The rank of binding free energies calculated with MM-GBSA not only agrees well with that determined by the experimental IC50 values but also suggests that mutual compensation between the enthalpy and entropy changes can improve binding of inhibitors to p38α. The analyses of free energy landscapes indicate that the L51, R24 and 1AU bound p38α display a DFG-out conformation. The residue-based free energy decomposition method is used to evaluate contributions of separate residues to the inhibitor-p38α binding and the results imply that residues V30, V38, L74, L75, I84, T106, H107, L108, M109, L167, F169 and D168 can be utilized as efficient targets of potent inhibitors toward p38α.

2021-01-01·American journal of translational research

miR-24 targets HMOX1 to regulate inflammation and neurofunction in rats with cerebral vasospasm after subarachnoid hemorrhage.

Article

作者: Zhang, Qi ; Liang, Chong ; Deng, Xiaodong ; Qian, Lei

OBJECTIVETo investigate the effects of miR-24 and HMOX1 on the inflammatory response and neurological function in rats with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH).METHODSFifteen Sprague-Dawley rats were randomly assigned to the sham group (sham operation, treated with normal saline). Rat model of SAH-induced CVS was established in 90 rats, and these rats were randomly divided into the model, miR-24 NC (treated with miR-24-NC vector), miR-24 inhibitor (treated with miR-24 inhibitor vector), HMOX-NC (treated with HMOX1-NC vector), oe-HMOX1 (treated with HMOX1 overexpression vector), and miR-24 inhibitor + si-HMOX1 (treated with miR-24 inhibitor and si-HMOX1 vectors) groups. Adenoviral vectors containing the target sequences were injected into the hippocampus of the rats in the corresponding groups. Dual-luciferase reporter assay was conducted to verify the relationship between miR-24 and HMOX1. The learning and memory abilities, neurological function, cerebral edema, permeability of blood-brain barrier, myeloperoxidase activity, and levels of miR-24, HMOX1, interleukin-6, tumor necrosis factor-α, superoxide dismutase, and malondialdehyde in rats were examined.RESULTSmiR-24 could negatively regulate HMOX1 expression. SAH-induced CVS was accompanied with increased miR-24 expression and decreased HMOX1 expression. Inhibiting miR-24 expression or enhancing the expression of its down streaming target, HMOX1, could partly reverse the increased oxidation and inflammation as well as functional deficits in the rats. Moreover, the effects of miR-24 inhibitor could be reversed by inhibiting HMOX1 expression.CONCLUSIONmiR-24 downregulation can promote HMOX1 expression, thereby decreasing the inflammatory response and improving the neurological function of rats with CVS after SAH.

2018-06-01·Gene3区 · 生物学

MicroRNA-24 regulates vascular remodeling via inhibiting PDGF-BB pathway in diabetic rat model

3区 · 生物学

Article

作者: Wang, Huibo ; Ding, Jiawang ; Yang, Jun ; Liu, Xiaowen ; Zeng, Ping ; Yang, Jian ; Chen, Lihua

PURPOSEHyperglycemia is the high risk factor of vascular remodeling induced by angioplasty, and neointimal hyperplasia is strongly implicated in the pathogenesis of vascular remodeling caused by carotid artery balloon injury. Studies have shown that MicroRNA 24 (miR-24) plays an important role in angiocardiopathy, However, the role of miR-24 is far from thorough research. In this study, we investigate whether up-regulation of miR-24 by using miR-24 recombinant adenovirus (Ad-miR-24-GFP) can inhibit PDGF-BB signaling pathway and attenuate vascular remodeling in the diabetic rat model.METHODSMale Sprague-Dawley rats (n = 60) were randomly divided into 5 groups and fed with high sugar and high fat diet (Sham, Saline, Scramble, Ad-miR-24 groups), or ordinary diet (Control group). The front four groups were treated with streptozotocin (STZ) four weeks later and the blood glucose level was closely monitored. After the successful establishment of diabetic rats, the external carotid artery was injured by pressuring balloon 1.5 after internal carotid artery ligation, then the blood vessels were harvested 14 days later and indexes were detected including the following: HE staining for the level of vascular intima thickness, immunohistochemical detection for PCNA and P27 to test the proliferative degree of vascular smooth muscle cells (VSMCs), qRT-PCR for the level of miR-24, RAS,PDGF-R, western blot for the protein levels of JNK1/2, p- JNK1/2, ERK1/2, p-ERK1/2, RAS, PDGF-R, AP-1,P27 and PCNA. Serological detection was conducted for TNF-α, IL-6, IL-8.RESULTSThe delivery of Ad-miR-24 into balloon injury site has significantly increased the level of miR-24. Up-regulation of miR-24 could regulate vascular remodeling effectively, lower the level of inflammatory factors, inhibit the expression of mRNA and protein levels of JNK1/2, ERK1/2, RAS, PDGF-R, AP-1, P27, PCNA.CONCLUSIONmiR-24 can inhibit the expression of AP-1 via the inhibition of PDGF-BB signaling pathway, thus inhibit VSMCs proliferation and vascular remodeling.

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