2. Academic Validation
  3. Molecular Determinants of EphA2 and EphB2 Antagonism Enable the Design of Ligands with Improved Selectivity

Molecular Determinants of EphA2 and EphB2 Antagonism Enable the Design of Ligands with Improved Selectivity

  • J Chem Inf Model. 2023 Nov 13;63(21):6900-6911. doi: 10.1021/acs.jcim.3c01064.
Lorenzo Guidetti 1,  Alfonso Zappia 1,  Laura Scalvini 1,  Francesca Romana Ferrari 1,  Carmine Giorgio 1,  Riccardo Castelli 1,  Francesca Galvani 1,  Federica Vacondio 1,  Silvia Rivara 1,  Marco Mor 1 2,  Chiara Urbinati 3,  Marco Rusnati 3,  Massimiliano Tognolini 1,  Alessio Lodola 1
Affiliations

Affiliations

  • 1 Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I- 43124 Parma, Italy.
  • 2 Microbiome Research Hub, Università degli Studi di Parma, Parco Area delle scienze 11/A, I- 43124 Parma, Italy.
  • 3 Dipartimento di Medicina Molecolare Traslazionale, Università degli Studi di Brescia, Brescia 25121, Italy.
PMID: 37910792 DOI: 10.1021/acs.jcim.3c01064
Abstract

With the aim of identifying novel antagonists selective for the EphA receptor family, a combined experimental and computational approach was taken to investigate the molecular basis of the recognition between a prototypical Eph-ephrin antagonist (UniPR1447) and two representative receptors of the EphA and EphB subfamilies, namely, EphA2 and EphB2 receptors. The conformational free-energy surface (FES) of the binding state of UniPR1447 within the ligand binding domain of EphA2 and EphB2, reconstructed from molecular dynamics (MD) simulations performed on the microsecond time scale, was exploited to drive the design and synthesis of a novel antagonist selective for EphA2 over the EphB2 receptor. The availability of compounds with this pharmacological profile will help discriminate the importance of these two receptors in the insurgence and progression of Cancer.

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