TY - JOUR
T1 - A computational workflow for the design of irreversible inhibitors of protein kinases
AU - Rio, Alberto Del
AU - Sgobba, Miriam
AU - Parenti, Marco Daniele
AU - Degliesposti, Gianluca
AU - Forestiero, Rosetta
AU - Percivalle, Claudia
AU - Conte, Pier Franco
AU - Freccero, Mauro
AU - Rastelli, Giulio
PY - 2010/3
Y1 - 2010/3
N2 - 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.
AB - 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.
KW - Binding free energy
KW - Cysteine trap
KW - ERK2
KW - Generalized amber force field
KW - Irreversible inhibition
KW - Michael acceptors
KW - Molecular dynamics
KW - Protein kinases
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U2 - 10.1007/s10822-010-9324-x
DO - 10.1007/s10822-010-9324-x
M3 - Article
C2 - 20306284
AN - SCOPUS:77954945271
VL - 24
SP - 183
EP - 194
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
SN - 0920-654X
IS - 3
ER -