Binding Kinetics in Drug Discovery

Abstract

Over the last years, researchers have increasingly become interested in measuring and understanding drugs' binding kinetics, namely the time in which drug and its target associate and dissociate. Historically, drug discovery programs focused on the optimization of target affinity as a proxy of in-vivo efficacy. However, often the efficacy of a ligand is not appropriately described by the in-vitro measured drug-receptor affinity, but rather depends on the lifetime of the in-vivo drug-receptor interaction. In this review we review recent works that highlight the importance of binding kinetics, molecular determinants for rational optimization and the recent emergence of computational methods as powerful tools in measuring and understanding binding kinetics.

Comparison of the Human A2A Adenosine Receptor Recognition by Adenosine and Inosine: New Insight from Supervised Molecular Dynamics Simulations

“…Short simulations are perpetuated under the supervision until the distance between the ligand and the binding site drops below 5 Å, then the supervision is disabled and a classical MD simulation is performed. From a general point of view, SuMD can be considered an adaptive sampling method during which unbiased simulation are run consecutively, instead that in parallel as usually done …”

“…Short simulations are perpetuated under the supervision until the distance between the ligand and the binding site drops below 5 ,t hen the supervision is disabled and aclassical MD simulation is performed. From ag eneral point of view,S uMD can be considered an adaptive sampling method [53] during which unbiased simulation are run consecutively, instead that in parallel as usually done. [54] Docking simulations:I nosine structure was built using the MOEbuilder tool, which is part of the MOE suite, [41] and was subjected to energy minimization with MMFF94x force field until the rootmean-square (RMS) conjugate gradient was < 0.05 kcal mol À1 À1 .…”

Advanced simulation techniques for the thermodynamic and kinetic characterization of biological systems

“…Clearly, thermodynamics can be obtained from kinetics, but not vice versa, and a complete in silico picture of a biophysical process includes a detailed account of kinetics. The latter is particularly important in order to compare with experiments, examples being temperature-jump and fluorescence techniques for protein folding [119] or surface plasmon resonance for protein-ligand interaction [120,121].…”

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

“…The essence of T-REMD and H-REMD is to exchange relatively higher-energy with lower-energy states and vice versa by means of the Metropolis criterion[65]. These methods can offer a sampling of about 50–100 times more relevant data than standard MD simulations started from the same initial configurations[66, 67]. These techniques can be expensive, since they may require few thousands of CPUs or hundreds of GPUs to distribute among many replicas of ion channel systems.…”