title: Metadynamics Simulations Distinguish Short- and Long-Residence-Time Inhibitors of Cyclin-Dependent Kinase 8.
abstract: The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle scienze 27/A, 43124 Parma, Italy.
authors.forename: Donatella
authors.identifier: 0000-0002-2574-3826
authors.initials: D
authors.lastname: Callegari
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle scienze 27/A, 43124 Parma, Italy.
authors.forename: Alessio
authors.identifier: 0000-0002-8675-1002
authors.initials: A
authors.lastname: Lodola
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle scienze 27/A, 43124 Parma, Italy.
authors.forename: Daniele
authors.identifier: 0000-0001-6160-6127
authors.initials: D
authors.lastname: Pala
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle scienze 27/A, 43124 Parma, Italy.
authors.forename: Silvia
authors.identifier: 0000-0001-8058-4250
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma , Viale delle scienze 27/A, 43124 Parma, Italy.
authors.forename: Marco
authors.identifier: 0000-0003-0199-1849
authors.initials: M
authors.lastname: Mor
authors.affiliation: Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A. , Largo F. Belloli 11/A, 43122 Parma, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rizzi
authors.affiliation: Chemistry Research and Drug Design Department, Chiesi Farmaceutici S.p.A. , Largo F. Belloli 11/A, 43122 Parma, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Capelli
mesh_terms: D056850:Cyclin-Dependent Kinase 8 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D056850:Cyclin-Dependent Kinase 8