title: Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications.
abstract: Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, β, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the β subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the β-isoform do not interact directly with either PI3Kβ or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.
authors.affiliation: Schrodinger , 120 W 45th St, New York, New York 10036, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Robinson
authors.forename: Thomas
authors.initials: T
authors.lastname: Bertrand
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Carry
authors.forename: Frank
authors.initials: F
authors.lastname: Halley
authors.forename: Andreas
authors.initials: A
authors.lastname: Karlsson
authors.forename: Magali
authors.initials: M
authors.lastname: Mathieu
authors.forename: Hervé
authors.initials: H
authors.lastname: Minoux
authors.forename: Marc-Antoine
authors.initials: MA
authors.lastname: Perrin
authors.forename: Benoit
authors.initials: B
authors.lastname: Robert
authors.forename: Laurent
authors.initials: L
authors.lastname: Schio
authors.affiliation: Schrodinger , 120 W 45th St, New York, New York 10036, United States.
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
mesh_terms: D008024:Ligands; D056004:Molecular Dynamics Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism*; D012997:Solvents / Q000737:chemistry*; D013379:Substrate Specificity; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D008024:Ligands; D021122:Protein Subunits; D012997:Solvents; D014867:Water; D019869:Phosphatidylinositol 3-Kinases