Conspectus A principal goal of drug discovery project is to design molecules that can tightly
and selectively bind to the target protein receptor. Accurate prediction of protein–ligand …

Ligand/protein binding (LPB) is a major topic in medicine, chemistry and biology. Since the
advent of computers, many scientists have put efforts in develo** theoretical models that …

Designing tight-binding ligands is a primary objective of small-molecule drug discovery.
Over the past few decades, free-energy calculations have benefited from improved force …

Protein structural biology came a long way since the determination of the first three-
dimensional structure of myoglobin about six decades ago. Across this period, X-ray …

Highlights•Free energy calculations and computational solvent analysis guiding drug
discovery.•Drug discovery programs targeting acetyl-CoA carboxylase and tyrosine kinase …

Relative alchemical binding free energy calculations are routinely used in drug discovery
projects to optimize the affinity of small molecules for their drug targets. Alchemical methods …

We evaluated the utility of a variant of the replica exchange method, a replica exchange with
hybrid tempering (REHT), for all-atom explicit water biomolecular simulations and compared …

The authors propose a novel method to evaluate the position-dependent diffusion constant
by analyzing unperturbed segments of a trajectory determined by the additional flat-bottom …

Recent advances in improved force fields and sampling methods have made it possible for
the accurate calculation of protein–ligand binding free energies. Alchemical free energy …

Significant improvements have been made in the past decade to methods that rapidly and
accurately predict binding affinity through free energy perturbation (FEP) calculations. This …