title: Computational Approaches to the Chemical Equilibrium Constant in Protein-ligand Binding.
abstract: The physiological role played by protein-ligand recognition has motivated the development of several computational approaches to the ligand binding affinity. Some of them, termed rigorous, have a strong theoretical foundation but involve too much computation to be generally useful. Some others alleviate the computational burden by introducing strong approximations and/or empirical calibrations, which also limit their general use. Most importantly, there is no straightforward correlation between the predictive power and the level of approximation introduced. Here, we present a general framework for the quantitative interpretation of protein-ligand binding based on statistical mechanics. Within this framework, we re-derive self-consistently the fundamental equations of some popular approaches to the binding constant and pinpoint the inherent approximations. Our analysis represents a first step towards the development of variants with optimum accuracy/efficiency ratio for each stage of the drug discovery pipeline.
authors.affiliation: Laboratoire d'Ingénierie des Fonctions Moléculaires ISIS, UMR 7006 CNRS, Université de Strasbourg, F-67083, Strasbourg Cedex, France.
authors.forename: Joel José
authors.initials: JJ
authors.lastname: Montalvo-Acosta
authors.affiliation: Laboratoire d'Ingénierie des Fonctions Moléculaires ISIS, UMR 7006 CNRS, Université de Strasbourg, F-67083, Strasbourg Cedex, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Cecchini
mesh_terms: D019295:Computational Biology / Q000379:methods; D055808:Drug Discovery / Q000379:methods; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins
keywords: binding affinity; free energy calculations; molecular recognition; protein-ligand binding; rational drug design