Simulation of ligand dissociation kinetics from the protein kinase PYK2

Abstract

Early-stage drug discovery projects often focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. The kinetics of drug binding are ignored but can have significant influence on drug efficacy. Therefore, increasing attention has been paid on evaluating drug-binding kinetics early in a drug discovery process. Simulating drug-binding kinetics at the atomic level is challenging for the long time scale involved. Here, we used the transition-based reweighting analysis method (TRAM) with the Markov state model to study the dissociation of a ligand from the protein kinase PYK2. TRAM combines biased and unbiased simulations to reduce computational costs. This work used the umbrella sampling technique for the biased simulations. Although using the potential of mean force from umbrella sampling simulations with the transition-state theory over-estimated the dissociation rate by three orders of magnitude, TRAM gave a dissociation rate within an order of magnitude of the experimental value.

Manifold learning in atomistic simulations: a conceptual review

“…TICA and it variants have been used to study molecular kinetics [17,172,173], free-energy estimation, finding slow CVs [8,56,159,174], enhanced sampling [166,168,169], and analysis of complex processes [160,[175][176][177][178][179][180][181][182][183][184][185][186][187][188][189][190][191]. For more applications, we refer to reviews [192][193][194].…”

Selectivity and Ranking of Tight-Binding JAK-STAT Inhibitors Using Markovian Milestoning with Voronoi Tessellations

“…Molecular dynamics (MD) simulations have been effective in studying the binding and unbinding dynamics of protein–-inhibitor complexes and can be used for kinetic estimates. − Understanding the receptor–ligand binding and unbinding process can be useful for drug discovery and development, especially in accelerating lead optimization efforts and lowering drug attrition rates. − The bimolecular association rate constant ( k on ) and the dissociation rate constant ( k off ) are required to describe the kinetic profile of a potential noncovalent inhibitor or a drug molecule. Recently, drug–target residence time (1/ k off ), or the time spent by the drug in the binding pocket of the protein, has received significant attention as drugs with a higher residence time are shown to have greater in vivo efficacy as compared to thermodynamic parameters such as free energy. − It is possible for drugs with similar binding free energies (Δ G bind ) to have different binding and unbinding kinetic rates.…”

Characterization of binding kinetics and intracellular signaling of new psychoactive substances targeting cannabinoid receptor using transition-based reweighting method

“…49,50 Furthermore, TRAM have been utilized for thermodynamics and kinetics estimations of ligand (un)binding for kinase and Serine protease. 48,51 To implement TRAM for our study, extensive sampling of the (un)binding process of both ligands was performed using a combination of umbrella sampling and unbiased simulations from the pathway obtained using metadynamics (see Methods section). 52 We showed that TRAM can produce consistent kinetic estimation with less unbiased simulation data compared to traditional methods like the Markov state model.…”