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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
Summary
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.
- 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.
