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Updated: May 28, 2026

A Bilingual Computational Workflow for Identifying Potential PLK1 Inhibitors in American Sign Language and English
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A Multi-Step Computational Workflow for Screening and Prioritizing SHP2-Binding Molecules.

Marina Bilotta1, Roberta Rocca1,2, Stefano Alcaro1,2

  • 1Dipartimento di Scienze Della Salute, Università "Magna Græcia" di Catanzaro, Campus "S. Venuta", 88100 Catanzaro, Italy.

Pharmaceuticals (Basel, Switzerland)
|May 27, 2026
PubMed
Summary
This summary is machine-generated.

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A novel computational strategy successfully identified compound 4 as a promising SHP2 inhibitor, overcoming challenges in targeting flexible protein pockets and conserved water networks for cancer therapy.

Area of Science:

  • Biochemistry and Structural Biology
  • Computational Chemistry and Drug Discovery

Background:

  • SHP2 (PTPN11) is a critical regulator of RAS/MAPK signaling, implicated in cancer and developmental disorders.
  • Designing effective SHP2 ligands is difficult due to the protein's flexible active site and essential water molecules.

Purpose of the Study:

  • To develop and apply a computational workflow for identifying and prioritizing novel SHP2-binding candidates.
  • To address the challenges posed by SHP2's flexible pocket and conserved water network in ligand design.

Main Methods:

  • Integrative computational approach: water-aware docking, virtual screening (714,409 compounds), MM/GBSA, AI (ChemBERTa), and molecular dynamics (MD) simulations.
  • Analysis of conserved water molecules (W711, W716, W726, W776) crucial for ligand binding.
Keywords:
MM/GBSASHP2chemical space modelingligand prioritizationmolecular dynamicsstructural waterstransformer embeddingsvirtual screening

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08:45

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  • Prioritization based on docking scores, physicochemical properties, structural analysis, and binding free energy.

    • Main Results:

    • Seven compounds were selected, with compound 4 showing favorable drug-likeness and GI absorption.
    • ChemBERTa revealed significant structural novelty for the identified candidates.
    • 1 μs MD simulations indicated stable binding of compound 4 with conserved water interactions.

    Conclusions:

    • Compound 4 is prioritized as a promising, structurally novel SHP2-binding candidate.
    • The integrative computational strategy is generalizable for targeting challenging proteins with flexible pockets and water networks.