Drug-target binding represents the first event at the basis of the therapeutic action of drugs. This complex phenomenon needs to be properly described at an atomistic level to identify the major determinants of drug potency and in vivo drug efficacy. Molecular dynamics (MD) is emerging as a powerful tool for investigating protein-ligand binding, and is getting increasing consensus from the drug discovery community. While extensive MD simulations in the microsecond to the millisecond timescale are nowadays able to simulate protein-ligand binding “spontaneously”, enhanced sampling methods, including metadynamics, steered-MD, umbrella sampling, etc., can improve the sampling of that part of free energy landscape that can be relevant for the biological process under investigation.
In this talk, I will be presenting the use of extensive MD simulations to investigate spontaneous protein-ligand binding. Then, I will show how free energy calculations allow the identification of the minimum free energy path from the bulk of the solvent into the protein-binding pocket, as well as the determination of thermodynamic and kinetic parameters associated to drug-target recognition and binding. The presentation will finally be focused on applications of enhanced sampling methods to accelerate ligand binding and unbinding and to estimate kinetics (kon and koff) and thermodynamics, in simulation timescale more compatible with the requirements of speed and accuracy of the pharmaceutical research. All these simulations will be discussed in the framework of drug design and discovery, highlighting the role of these approaches in real-life drug discovery endeavors.