title: Alchemical free energy methods for drug discovery: progress and challenges.
abstract: Improved rational drug design methods are needed to lower the cost and increase the success rate of drug discovery and development. Alchemical binding free energy calculations, one potential tool for rational design, have progressed rapidly over the past decade, but still fall short of providing robust tools for pharmaceutical engineering. Recent studies, especially on model receptor systems, have clarified many of the challenges that must be overcome for robust predictions of binding affinity to be useful in rational design. In this review, inspired by a recent joint academic/industry meeting organized by the authors, we discuss these challenges and suggest a number of promising approaches for overcoming them.
authors.affiliation: California Institute of Quantitative Biosciences (QB3), University of California, Berkeley, 260J Stanley Hall, Berkeley, CA 94720, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Chodera
authors.forename: David L
authors.initials: DL
authors.lastname: Mobley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Shirts
authors.forename: Richard W
authors.initials: RW
authors.lastname: Dixon
authors.forename: Kim
authors.initials: K
authors.lastname: Branson
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D019295:Computational Biology / Q000379:methods; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D011506:Proteins