New approaches for computing ligand–receptor binding kinetics

• Published in: Current opinion in structural biology 2018-04, Vol.49, p.1-10
• Main Authors: Bruce, Neil J, Ganotra, Gaurav K, Kokh, Daria B, Sadiq, S Kashif, Wade, Rebecca C
• Format: Article
• Language: English
• Subjects: Animals; Drug Discovery - methods; Humans; Kinetics; Ligands; Molecular Docking Simulation - methods; Molecular Dynamics Simulation; Protein Binding; Protein Conformation - drug effects; Proteins - chemistry; Proteins - metabolism; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Thermodynamics
• ISSN: 0959-440X; 1879-033X
• DOI: 10.1016/j.sbi.2017.10.001

•Many new approaches to computing biomolecular binding kinetics developed recently.•Enhanced sampling simulation methods permit long-time binding kinetics to be studied.•Combined physics-based and chemometric approaches offer promise for deriving QSKRs.•A toolbox of diverse methods to compute ligand binding kinetics is needed. The recent and growing evidence that the efficacy of a drug can be correlated to target binding kinetics has seeded the development of a multitude of novel methods aimed at computing rate constants for receptor–ligand binding processes, as well as gaining an understanding of the binding and unbinding pathways and the determinants of structure–kinetic relationships. These new approaches include various types of enhanced sampling molecular dynamics simulations and the combination of energy-based models with chemometric analysis. We assess these approaches in the light of the varying levels of complexity of protein–ligand binding processes.