A computational workflow for the design of irreversible inhibitors of protein kinases

Alberto Del Rio, Miriam Sgobba, Marco Daniele Parenti, Gianluca Degliesposti, Rosetta Forestiero, Claudia Percivalle, Pier Franco Conte, Mauro Freccero, Giulio Rastelli

Research output: Contribution to journalArticlepeer-review


Design of irreversible inhibitors is an emerging and relatively less explored strategy for the design of protein kinase inhibitors. In this paper, we present a computational workflow that was specifically conceived to assist such design. The workflow takes the form of a multi-step procedure that includes: the creation of a database of already known reversible inhibitors of protein kinases, the selection of the most promising scaffolds that bind one or more desired kinase templates, the modification of the scaffolds by introduction of chemically reactive groups (suitable cysteine traps) and the final evaluation of the reversible and irreversible protein-ligand complexes with molecular dynamics simulations and binding free energy predictions. Most of these steps were automated. In order to prove that this is viable, the workflow was tested on a database of known inhibitors of ERK2, a protein kinase possessing a cysteine in the ATP site. The modeled ERK2-ligand complexes and the values of the estimated binding free energies of the putative ligands provide useful indicators of their aptitude to bind reversibly and irreversibly to the protein kinase. Moreover, the computational data are used to rank the ligands according to their computed binding free energies and their ability to bind specific protein residues in the reversible and irreversible complexes, thereby providing a useful decision-making tool for each step of the design. In this work we present the overall procedure and the first proof of concept results.

Original languageEnglish
Pages (from-to)183-194
Number of pages12
JournalJournal of Computer-Aided Molecular Design
Issue number3
Publication statusPublished - Mar 2010


  • Binding free energy
  • Cysteine trap
  • ERK2
  • Generalized amber force field
  • Irreversible inhibition
  • Michael acceptors
  • Molecular dynamics
  • Protein kinases

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications


Dive into the research topics of 'A computational workflow for the design of irreversible inhibitors of protein kinases'. Together they form a unique fingerprint.

Cite this