Determination of promising inhibitors for N-SH2 domain of SHP2 tyrosine phosphatase: an in silico study

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Gencer Akçok E. B., Güner H., Akçok İ.

Molecular Diversity, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Publication Date: 2024
  • Doi Number: 10.1007/s11030-024-10880-2
  • Journal Name: Molecular Diversity
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, MEDLINE
  • Keywords: In silico, Molecular docking, Molecular dynamics (MD), SH2 domain, SHP2 phosphatase
  • Dokuz Eylül University Affiliated: No


There are many genes that produce proteins related to diseases and these proteins can be targeted with drugs as a potential therapeutic approach. Recent advancement in drug discovery techniques have created new opportunities for treating variety of diseases by targeting disease-related proteins. Structure-based drug discovery is a faster and more cost-effective approach than traditional methods. SHP2 phosphatase, encoded by the PTPN11 gene, has been the focus of much attention due to its involvement in many types of diseases. The biological function of SHP2 is enabled mostly by protein–protein interaction through its SH2 domains. In this study, we report the identification of a potential small molecule inhibitor for the N-SH2 domain of SHP2 by structure-based drug discovery approach. We utilized molecular docking studies, followed by molecular dynamics simulations and MM/PBSA calculations, to analyze compounds retrieved from the Broad's Drug Repurposing Hub and ZINC15 databases. We selected 10 hit compounds with the best docking scores from the libraries and examined their binding properties in the N-SH2 domain. We found that compound CID 60838 (Irinotecan) was the most suitable compound with a binding free energy value of − 64.45 kcal/mol and significant interactions with the target residues in the domain. Graphical abstract: (Figure presented.)