School of Electronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China.
Department of Pathology, College of Medicine, Imam Mohammad ibn Saud Islamic University, Riyadh, Saudi Arabia.
J Enzyme Inhib Med Chem. 2020 Dec;35(1):172-186. doi: 10.1080/14756366.2019.1692828.
Sphingosine kinase 1 (SphK1) is a promising therapeutic target against several diseases including mammary cancer. The aim of present work is to identify a potent lead compound against breast cancer using ligand-based virtual screening, molecular docking, MD simulations, and the MMPBSA calculations. The LBVS in molecular and virtual libraries yielded 20,800 hits, which were reduced to 621 by several parameters of drug-likeness, lead-likeness, and PAINS. Furthermore, 55 compounds were selected by ADMET descriptors carried forward for molecular interaction studies with SphK1. The binding energy (Δ) of three screened compounds namely ZINC06823429 (-11.36 kcal/mol), ZINC95421501 (-11.29 kcal/mol), and ZINC95421070 (-11.26 kcal/mol) exhibited stronger than standard drug PF-543 (-9.9 kcal/mol). Finally, it was observed that the ZINC06823429 binds tightly to catalytic site of SphK1 and remain stable during MD simulations. This study provides a significant understanding of SphK1 inhibitors that can be used in the development of potential therapeutics against breast cancer.
鞘氨醇激酶 1（SphK1）是一种有前途的治疗靶点，可用于治疗包括乳腺癌在内的多种疾病。本研究旨在使用基于配体的虚拟筛选、分子对接、MD 模拟和 MMPBSA 计算，鉴定一种针对乳腺癌的有效先导化合物。分子和虚拟文库中的 LBVS 产生了 20800 个命中物，通过药物相似性、先导相似性和 PAINS 的几个参数将其减少到 621。此外，通过 ADMET 描述符选择了 55 种化合物，这些化合物被进一步用于与 SphK1 的分子相互作用研究。三种筛选化合物 ZINC06823429（-11.36 kcal/mol）、ZINC95421501（-11.29 kcal/mol）和 ZINC95421070（-11.26 kcal/mol）的结合能（Δ）均强于标准药物 PF-543（-9.9 kcal/mol）。最后，观察到 ZINC06823429 紧密结合到 SphK1 的催化位点，并在 MD 模拟过程中保持稳定。这项研究为 SphK1 抑制剂的研究提供了重要的认识，可用于开发针对乳腺癌的潜在治疗药物。
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