1. Academic Validation
  2. Discovery of potent CSK inhibitors through integrated virtual screening and molecular dynamic simulation

Discovery of potent CSK inhibitors through integrated virtual screening and molecular dynamic simulation

  • Arch Pharm (Weinheim). 2024 May 29:e2400066. doi: 10.1002/ardp.202400066.
Roufen Chen 1 2 Yuchen Wang 2 Zheyuan Shen 2 Chenyi Ye 1 Yu Guo 2 Yan Lu 3 Jianjun Ding 4 Xiaowu Dong 2 3 Donghang Xu 3 Xiaoli Zheng 1
Affiliations

Affiliations

  • 1 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.
  • 2 Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
  • 3 Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 4 School of Food Science and Technology, Jiangnan University, Wuxi, China.
Abstract

Oncogenic overexpression or activation of C-terminal Src kinase (CSK) has been shown to play an important role in triple-negative breast Cancer (TNBC) progression, including tumor initiation, growth, metastasis, drug resistance. This revelation has pivoted the focus toward CSK as a potential target for novel treatments. However, until now, there are few inhibitors designed to target the CSK protein. Responding to this, our research has implemented a comprehensive virtual screening protocol. By integrating energy-based screening methods with AI-driven scoring functions, such as Attentive FP, and employing rigorous rescoring methods like Glide docking and molecular mechanics generalized Born surface area (MM/GBSA), we have systematically sought out inhibitors of CSK. This approach led to the discovery of a compound with a potent CSK inhibitory activity, reflected by an IC50 value of 1.6 nM under a homogeneous time-resolved fluorescence (HTRF) bioassay. Subsequently, molecule 2 exhibits strong growth inhibition of MD anderson - metastatic breast (MDA-MB) -231, Hs578T, and SUM159 cells, showing a level of growth inhibition comparable to that observed with dasatinib. Treatment with molecule 2 also induced significant G1 phase accumulation and cell Apoptosis. Furthermore, we have explored the explicit binding interactions of the compound with CSK using molecular dynamics simulations, providing valuable insights into its mechanism of action.

Keywords

CSK; MM/GBSA; attentive FP; triple‐negative breast cancer; virtual screening.

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