Here we present the design of the series of quercetin analogues and their molecular docking study involving the binding of quercetin and its analogues with SARS-CoV2 3CLpro. The scientific literature shows that quercetin compound has been successfully used against SARS-CoV by inhibiting the replication of virus in respiratory epithelial cell through the inhibition of the SARS-CoV main protease (3CLpro.) It was suggested that the modification at position 3 in quercetin structure may produce potent compounds against SARS-CoV2. A series of quercetin analogues were designed and screened for physicochemical and pharmacokinetics parameters. The activities of selected compounds against SARS-CoV2 were screened by molecular modelling and evaluated that analogues, Q5, Q6 and Q13 have the best docking scores (-8.01 to -8.17 kcal/mol) and also better than quercetin, α-ketoamide and current available inhibitors of the same target. The structure-activity relationship (SAR) study revealed that the introduction of the amino group in a designed molecule was highly promising for increasing the inhibitory activity against SARS-CoV2 3CL pro. Moreover, to check the stability and orientation of selected compounds inside the binding pocket, the molecular dynamic simulations were performed for 100 ns. Results revealed that the designed analogues Q1, Q6 and Q13 having lowest binding energies (-8.0, -8.17 and -8.06 kcal/mol respectively) as well as better physicochemical properties, pharmacokinetics, and toxicity profile show their potential to synthesize and develop as the therapeutic agents against corona virus.Communicated by Ramaswamy H. Sarma.

2023-06-07·The Journal of chemical physics

Protein-ligand interactions from a quantum fragmentation perspective: The case of the SARS-CoV-2 main protease interacting with α-ketoamide inhibitors.

Article

作者: Cristiglio, Viviana ; Vallet, Valérie ; Dawson, William ; Genovese, Luigi ; Nakajima, Takahito ; Masella, Michel

We present a hybrid, multi-method, computational scheme for protein/ligand systems well suited to be used on modern and forthcoming massively parallel computing systems. The scheme relies on a multi-scale polarizable molecular modeling, approach to perform molecular dynamics simulations, and on an efficient Density Functional Theory (DFT) linear scaling method to post-process simulation snapshots. We use this scheme to investigate recent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2 virus. We assessed the reliability and the coherence of the hybrid scheme, in particular, by checking the ability of MM and DFT to reproduce results from high-end ab initio computations regarding such inhibitors. The DFT approach enables an a posteriori fragmentation of the system and an investigation into the strength of interaction among identified fragment pairs. We show the necessity of accounting for a large set of plausible protease/inhibitor conformations to generate reliable interaction data. Finally, we point out ways to further improve α-ketoamide inhibitors to more strongly interact with particular protease domains neighboring the active site.

2023-04-04·Nutrients

Glyoxylic Acid, an α-Keto Acid Metabolite Derived from Glycine, Promotes Myogenesis in C2C12 Cells.

Article

作者: Kojima-Yuasa, Akiko ; Norikura, Toshio ; Sasaki, Yutaro ; Kon, Atsushi

α-Keto acids may help prevent malnutrition in patients with chronic kidney disease (CKD), who consume protein-restricted diets, because they serve as amino acid sources without producing nitrogenous waste compounds. However, the physiological roles of α-keto acids, especially those derived from non-essential amino acids, remain unclear. In this study, we examined the effect of glyoxylic acid (GA), an α-keto acid metabolite derived from glycine, on myogenesis in C2C12 cells. Differentiation and mitochondrial biogenesis were used as myogenesis indicators. Treatment with GA for 6 d resulted in an increase in the expression of differentiation markers (myosin heavy chain II and myogenic regulatory factors), mitochondrial biogenesis, and intracellular amounts of amino acids (glycine, serine, and alanine) and their metabolites (citric acid and succinic acid). In addition, GA treatment suppressed the 2.5-µM dexamethasone (Dex)-induced increase in mRNA levels of ubiquitin ligases (Trim63 and Fbxo32), muscle atrophy markers. These results indicate that GA promotes myogenesis, suppresses Dex-induced muscle atrophy, and is metabolized to amino acids in muscle cells. Although further in vivo experiments are needed, GA may be a beneficial nutrient for ameliorating the loss of muscle mass, strength, and function in patients with CKD on a strict dietary protein restriction.

项与 GC-375 相关的新闻（医药）

2023-02-22

·生物制品圈

武汉病毒所等团队在穿山甲中发现了可感染人类的冠状病毒

我国科学家在非法走私的马来亚穿山甲中发现了一种新的MERS样蝙蝠冠状病毒（CoV），它可以感染人类细胞并在其中复制，表明它也许会跳到人类身上并引发疾病。这篇题为“A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry”的论文于2月16日发表在Cell杂志上，通讯作者包括中科院武汉病毒研究所周鹏和石正丽、广西医科大学胡艳玲、北京化工大学童贻刚以及复旦大学林鑫华。这项研究表明，穿山甲携带的MERS样冠状病毒与蝙蝠有关，但与蝙蝠病毒相比，它能够直接感染人类，而且对人类的传染性增强，这表明穿山甲在人类冠状病毒的出现中发挥重要作用。穿山甲是被贩卖最多的哺乳动物之一，经常与人类接触。之前的研究在从马来西亚走私到中国的穿山甲中发现了与新型冠状病毒（SARS-CoV-2）相关的谱系。新冠大流行已持续了快三年时间，但目前仍不清楚人类是如何首次感染SARS-CoV-2的。在这项新研究中，研究人员采集了从东南亚非法走私到中国的86只马来亚穿山甲的肛拭子样本，并采用一种泛CoV PCR检测对其进行筛选。其中，4个样本呈CoV阳性。接下来，他们对阳性样本进行测序，并组装出四个几乎相同的全长冠状病毒基因组。系统发育分析显示，这种新病毒是一种MERS样冠状病毒，与蝙蝠HKU4-CoV有亲缘关系。研究人员将它命名为MjHKU4r-CoV（马来亚穿山甲HKU4相关冠状病毒）。之后的细胞培养实验表明，这种病毒能够感染人类细胞，以人类二肽基肽酶-4（hDPP4）受体作为落脚点来进入细胞。此外，新病毒的刺突蛋白上有一个furin蛋白酶裂解位点，通过蛋白酶切割而增强了其感染人类细胞的能力。此外，MjHKU4r-CoV还能够进入人类呼吸道和肠道类器官，并在其中进行复制，表明它能够通过这一途径感染人类。它还可以通过鼻腔感染hDDP4转基因小鼠，并在动物体内引起疾病。最后，研究人员测试了MjHKU4r-CoV感染的潜在治疗方法。他们发现，GC375、瑞德西韦等小分子药物对这种病毒都表现出抗病毒活性。然而，对MERS-CoV表现出良好中和活性的三种单克隆抗体却对新病毒没有效果，未表现出中和活性。这项研究的局限性之一是，研究人员无法确定新病毒是直接从蝙蝠外溢到穿山甲，还是有其他野生动物参与。他们没有检测到目前是否有外溢到人类的情况，但建议对人类进行监测，因为该病毒“对人类有潜在的传染性和致病性”。作者在文中总结道：“为了更好地了解穿山甲作为蝙蝠相关CoV的病毒库或易感宿主的作用，并为穿山甲MERS样CoV的出现更好地做准备，未来需要进行监测。”参考文献：A bat MERS-like coronavirus circulates in pangolins and utilizes human DPP4 and host proteases for cell entry

100 项与 GC-375 相关的药物交易

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