Computer-Aided Drug Design Boosts RAS Inhibitor Discovery

Wang, Ge; Bai, Yang; Cui, Jiarui; Zong, Zirui; Gao, Yuan; Zhao, Zheng

doi:10.3390/molecules27175710

Cited by 6 publications

(1 citation statement)

References 146 publications

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“…They have resolved distinct steps in the GDP–GTP cycle, how they affect RAS protein conformation [ 151 ], and the interaction with effectors [ 152 ]. They also facilitate finding drug binding pockets and the design of RAS inhibitors [ 153 ]. (2) RAS activation dynamics.…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of RAS and RAS signaling

Kölch

Berta

Rosta

2023

Biochemical Journal

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RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.

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Section: Discussionmentioning

confidence: 99%

Dynamic regulation of RAS and RAS signaling

Kölch

Berta

Rosta

2023

Biochemical Journal

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Computational biology-based study of the molecular mechanism of spermidine amelioration of acute pancreatitis

Shen,

Duan,

Yuan

et al. 2023

Mol Divers

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Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

Zheng,

Hao,

Medrano-Garcia

et al. 2023

Cell Death Dis

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Progressive hepatic damage and fibrosis are major features of chronic liver diseases of different etiology, yet the underlying molecular mechanisms remain to be fully defined. N-RAS, a member of the RAS family of small guanine nucleotide-binding proteins also encompassing the highly homologous H-RAS and K-RAS isoforms, was previously reported to modulate cell death and renal fibrosis; however, its role in liver damage and fibrogenesis remains unknown. Here, we approached this question by using N-RAS deficient (N-RAS−/−) mice and two experimental models of liver injury and fibrosis, namely carbon tetrachloride (CCl4) intoxication and bile duct ligation (BDL). In wild-type (N-RAS+/+) mice both hepatotoxic procedures augmented N-RAS expression in the liver. Compared to N-RAS+/+ counterparts, N-RAS−/− mice subjected to either CCl4 or BDL showed exacerbated liver injury and fibrosis, which was associated with enhanced hepatic stellate cell (HSC) activation and leukocyte infiltration in the damaged liver. At the molecular level, after CCl4 or BDL, N-RAS−/− livers exhibited augmented expression of necroptotic death markers along with JNK1/2 hyperactivation. In line with this, N-RAS ablation in a human hepatocytic cell line resulted in enhanced activation of JNK and necroptosis mediators in response to cell death stimuli. Of note, loss of hepatic N-RAS expression was characteristic of chronic liver disease patients with fibrosis. Collectively, our study unveils a novel role for N-RAS as a negative controller of the progression of liver injury and fibrogenesis, by critically downregulating signaling pathways leading to hepatocyte necroptosis. Furthermore, it suggests that N-RAS may be of potential clinical value as prognostic biomarker of progressive fibrotic liver damage, or as a novel therapeutic target for the treatment of chronic liver disease.

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Computer-Aided Drug Design Boosts RAS Inhibitor Discovery

Cited by 6 publications

References 146 publications

Dynamic regulation of RAS and RAS signaling

Dynamic regulation of RAS and RAS signaling

Computational biology-based study of the molecular mechanism of spermidine amelioration of acute pancreatitis

Neuroblastoma RAS viral oncogene homolog (N-RAS) deficiency aggravates liver injury and fibrosis

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