title: Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field.
abstract: 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 fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.
authors.affiliation: Schrödinger, Inc. , 120 West 45th Street, New York, New York 10036, United States.
authors.forename: Lingle
authors.initials: L
authors.lastname: Wang
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wu
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Deng
authors.forename: Byungchan
authors.initials: B
authors.lastname: Kim
authors.forename: Levi
authors.initials: L
authors.lastname: Pierce
authors.forename: Goran
authors.initials: G
authors.lastname: Krilov
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lupyan
authors.forename: Shaughnessy
authors.initials: S
authors.lastname: Robinson
authors.forename: Markus K
authors.initials: MK
authors.lastname: Dahlgren
authors.forename: Jeremy
authors.initials: J
authors.lastname: Greenwood
authors.forename: Donna L
authors.initials: DL
authors.lastname: Romero
authors.forename: Craig
authors.initials: C
authors.lastname: Masse
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Knight
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinbrecher
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Damm
authors.forename: Ed
authors.initials: E
authors.lastname: Harder
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.forename: Mark
authors.initials: M
authors.lastname: Brewer
authors.forename: Ron
authors.initials: R
authors.lastname: Wester
authors.forename: Mark
authors.initials: M
authors.lastname: Murcko
authors.forename: Leah
authors.initials: L
authors.lastname: Frye
authors.forename: Ramy
authors.initials: R
authors.lastname: Farid
authors.forename: Teng
authors.initials: T
authors.lastname: Lin
authors.forename: David L
authors.initials: DL
authors.lastname: Mobley
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Berne
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friesner
authors.forename: Robert
authors.initials: R
authors.lastname: Abel
mesh_terms: D019295:Computational Biology; D015195:Drug Design; D055808:Drug Discovery; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins