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.

A molecular dynamics investigation of CDK8/CycC and ligand binding: conformational flexibility and implication in drug discovery

“…Computational methods such as molecular dynamics (MD) allow for complementary approaches to understand the details of structural changes during the process of ligand binding. Callegari and coworkers ranked the residence time of a series of CDK8 type-II inhibitors using metadynamics and the ranking was roughly consistent with experimental data [31]. Xu et al, with 50 ns of all-atom MD studies of human CDK8, provided insights into two-point mutations, D173A and D189N, within the activation loop by using hydrogen bond (H-bond) dynamic study of the activation loop residues and the MM/PBSA method [32].…”

Ligand binding free energy and kinetics calculation in 2020

“…For instance, parallel‐tempering metadynamics has been used to identify energetically relevant states (i.e., minima, metastable and transition states) and refinement simulations based on plain MD and QM/MM calculations allowed estimating the k off of the anticancer drug imatinib to Src kinase within one order of magnitude of the experimental value . Metadynamics in its original formalism with constant Gaussian height was employed to simulate ligand unbinding of 10 arylpyrazole cyclin‐dependent kinase 8 inhibitors . In this case, the average simulation unbinding times obtained from metadynamics simulations, were used to classify the CDK8 inhibitors in short, medium, and long residence time inhibitors.…”

Recent Advances in CDK Inhibitors for Cancer Therapy

“…[88,89] It was noted that the in vitro potency of Type II CDK8 inhibitors did not translate to cell-based activity, such as with the well-known pan-kinase inhibitor as such, novel metadynamic stimulations have been developed using the arylpyrazole series. [91] It is hoped that the approach can be utilised in future CDK8 drug discovery projects.…”