通过高通量虚拟筛选鉴定新型 CDK 4/6 抑制剂,Letters in Drug Design & Discovery

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通过高通量虚拟筛选鉴定新型 CDK 4/6 抑制剂
Letters in Drug Design & Discovery ( IF 1.2 ) Pub Date : 2024-01-09 , DOI: 10.2174/0115701808273043231130100833
Abhijit Debnath ₁ , Rupa Mazumder ₁

Affiliation

背景：CDK4/6在细胞增殖调节中发挥着至关重要的作用，抑制该激酶可以有效阻止细胞生长和分裂的启动。然而，目前FDA批准的CDK4/6抑制剂存在生物利用度差、不良反应、成本高、可及性有限等局限性。因此，本研究旨在发现新型 CDK4/6 抑制剂，以克服与 FDA 批准的抑制剂相关的挑战。方法：为了鉴定潜在的 CDK4/6 抑制剂，我们进行了基于结构的虚拟筛选。Chem-space 和 Mcule 数据库已经过筛选，随后进行了一系列过滤步骤。这些步骤包括评估药物相似性、PAINS 警报、合成可及性评分、ADMET 特性、共识分子对接以及进行分子动力学模拟。结果:: 四种新化合物（CSC089414133、CSC091186116、CSC096023304、CSC101755872）已被确定为潜在的 CDK4/6 抑制剂。这些化合物与CDK4/6表现出很强的结合亲和力，具有类似药物的特征，没有PAINS警报，具有较低的合成可及性得分，表现出有效的ADMET特性，无毒，并且表现出高稳定性。结论:: 用已鉴定的化合物抑制 CDK4/6 可能会导致细胞增殖减少并促进癌细胞死亡。结果：四种化合物（CSC089414133、CSC091186116、CSC096023304、CSC101755872）被鉴定为潜在的 CDK4/6 抑制剂。这些化合物在CDK4/6的活性位点表现出强结合亲和力，具有类药物特征，无PAINS警报，具有较低的合成可及性评分，表现出有效的ADMET特性，无毒，并且表现出高稳定性。

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Identification of Novel CDK 4/6 Inhibitors by High-throughput Virtual Screening

Background:: CDK4/6 plays a crucial role in regulating cell proliferation, and inhibiting this kinase can effectively prevent the initiation of cell growth and division. However, current FDAapproved CDK4/6 inhibitors have limitations such as poor bioavailability, adverse effects, high cost, and limited accessibility. Thus, this research aimed to discover novel CDK4/6 inhibitors to overcome the challenges associated with FDA-approved inhibitors. Methods:: To identify potential CDK4/6 inhibitors, we have performed structure-based virtual screening. Chem-space and Mcule databases have been screened, followed by a series of filtering steps. These steps included assessing drug-likeness, PAINS alert, synthetic accessibility scores, ADMET properties, consensus molecular docking, and performing molecular dynamics simulations. Results:: Four new compounds (CSC089414133, CSC091186116, CSC096023304, CSC101755872) have been identified as potential CDK4/6 inhibitors. These compounds exhibited strong binding affinity with CDK4/6, possessed drug-like features, showed no PAINS alert, had a low synthetic accessibility score, demonstrated effective ADMET properties, were non-toxic, and exhibited high stability. Conclusion:: Inhibiting CDK4/6 with the identified compounds may lead to reduced cell proliferation and the promotion of cancer cell death. result: Four compounds (CSC089414133, CSC091186116, CSC096023304, CSC101755872) were identified as potential CDK4/6 inhibitors. These compounds exhibited strong binding affinity at the active site of CDK4/6, possessed drug-like features, showed no PAINS alert, had a low synthetic accessibility score, demonstrated effective ADMET properties, were non-toxic, and exhibited high stability.

更新日期：2024-01-09

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