Discovery of novel 2,8-diazaspiro[4.5]decan-1-one derivatives as potent RIPK1 kinase inhibitors

Niu, Ao; Lin, Lizhi; Zhang, Danyang; Jiang, Kaixuan; Weng, Dan; Zhou, Wenjia

doi:10.1016/j.bmc.2022.116686

Cited by 4 publications

(5 citation statements)

References 26 publications

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“…However, it has been observed that the receptor structure selected using this method does not consistently yield optimal screening accuracy. To address this limitation, Vina-GPU 2.1 incorporates an alternative cross-docking method [11], which offers improved selection through cross-validation. In this approach, each receptor structure is individually docked with ligands extracted from other structures (different PDB IDs).…”

Section: Methodsmentioning

confidence: 99%

“…Figure 1 illustrates the overall architecture of Vina-GPU 2.1, which involves four steps of optimization in both the screening pipeline and docking algorithm. The first step focuses on selecting the best structure of the target receptor using the cross-docking method [11]. If necessary, the second step involves identifying the potential binding pocket of the selected structure using the COACH-D method [14].…”

Section: A Overall Architecturementioning

confidence: 99%

“…Numerous approaches have been proposed to improve screening accuracy, focusing primarily on expanding the conformational search space [9] and optimizing the scoring function [10] during molecular docking. Moreover, our virtual screening experiments have highlighted the potential for enhancing screening accuracy through the improvement of the threedimensional structure quality of ligand and receptor molecules, as well as the data quality of docked pocket structures [11], [12]. These aspects warrant careful attention as they hold promise for augmenting screening accuracy.…”

Section: Introductionmentioning

confidence: 99%

“…To enhance docking accuracy , we employ different strategies to optimize the structures of receptors, binding pockets, and ligands. For receptors, we utilize a cross-docking scheme to identify the most suitable cocrystal structure for docking during the screening process [11]. This step helps ensure that the appropriate receptor structure is used for accurate docking.…”

Section: Introductionmentioning

confidence: 99%

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Vina-GPU 2.1: towards further optimizing docking speed and precision of AutoDock Vina and its derivatives

Tang,

Ding,

Zhu

et al. 2023

Preprint

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AutoDock Vina and its derivatives have established themselves as a prevailing pipeline for virtual screening in contemporary drug discovery. Our Vina-GPU method leverages the parallel computing power of GPUs to accelerate AutoDock Vina, and Vina-GPU 2.0 further enhances the speed of AutoDock Vina and its derivatives. Given the prevalence of large virtual screens in modern drug discovery, the improvement of speed and accuracy in virtual screening has become a longstanding challenge. In this study, we propose Vina-GPU 2.1, aimed at enhancing the docking speed and precision of AutoDock Vina and its derivatives through the integration of novel algorithms to facil-itate improved docking and virtual screening outcomes. Building upon the foundations laid by Vina-GPU 2.0, we introduce a novel algorithm, namely Reduced Iteration and Low Complexity BFGS (RILC-BFGS), designed to expedite the most time-consuming operation. Additionally, we implement grid cache optimization to further enhance the docking speed. Furthermore, we employ optimal strategies to individually optimize the structures of ligands, receptors, and binding pockets, thereby enhancing the docking precision. To assess the performance of Vina-GPU 2.1, we conduct extensive virtual screening experiments on three prominent targets, utilizing two fundamental compound libraries and seven docking tools. Our results demonstrate that Vina-GPU 2.1 achieves an average 4.97-fold acceleration in docking speed and an average 342% improvement in EF1% compared to Vina-GPU 2.0. The source code and tools for Vina-GPU 2.1 are freely available athttps://github.com/DeltaGroupNJUPT/Vina-GPU-2.1, accompanied by comprehensive instructions and illustrative examples.

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Section: Methodsmentioning

confidence: 99%

Section: A Overall Architecturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Vina-GPU 2.1: towards further optimizing docking speed and precision of AutoDock Vina and its derivatives

Tang,

Ding,

Zhu

et al. 2023

Preprint

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“…In addition, there is an active search and identification of new highly selective inhibitors of RIPK1. For example, several new inhibitors have been described in the first quarter of 2022 (Delehouzé et al, 2022;Li et al, 2022b;Niu et al, 2022).…”

Section: Ripk1 Inhibitorsmentioning

confidence: 99%

Necroptosis in CNS diseases: Focus on astrocytes

Митрошина

Savyuk

Vedunova

2023

Front. Aging Neurosci.

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In the last few years, necroptosis, a recently described type of cell death, has been reported to play an important role in the development of various brain pathologies. Necroptosis is a cell death mechanism that has morphological characteristics similar to necrosis but is mediated by fundamentally different molecular pathways. Necroptosis is initiated by signaling through the interaction of RIP1/RIP3/MLKL proteins (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3/mixed lineage kinase domain-like protein). RIPK1 kinase is usually inactive under physiological conditions. It is activated by stimulation of death receptors (TNFR1, TNFR2, TLR3, and 4, Fas-ligand) by external signals. Phosphorylation of RIPK1 results in the formation of its complex with death receptors. Further, complexes with the second member of the RIP3 and MLKL cascade appear, and the necroptosome is formed. There is enough evidence that necroptosis plays an important role in the pathogenesis of brain ischemia and neurodegenerative diseases. In recent years, a point of view that both neurons and glial cells can play a key role in the development of the central nervous system (CNS) pathologies finds more and more confirmation. Astrocytes play complex roles during neurodegeneration and ischemic brain damage initiating both impair and protective processes. However, the cellular and molecular mechanisms that induce pathogenic activity of astrocytes remain veiled. In this review, we consider these processes in terms of the initiation of necroptosis. On the other hand, it is important to remember that like other types of programmed cell death, necroptosis plays an important role for the organism, as it induces a strong immune response and is involved in the control of cancerogenesis. In this review, we provide an overview of the complex role of necroptosis as an important pathogenetic component of neuronal and astrocyte death in neurodegenerative diseases, epileptogenesis, and ischemic brain damage.

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