Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications

详细信息    查看全文

• 作者：Daniel Robinson ; Thomas Bertrand ; Jean-Christophe Carry ; Frank Halley ; Andreas Karlsson ; Magali Mathieu ; Hervé Minoux ; Marc-Antoine Perrin ; Benoit Robert ; Laurent Schio ; Woody Sherman
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2016
• 出版时间：May 23, 2016
• 年：2016
• 卷：56
• 期：5
• 页码：886-894
• 全文大小：534K
• 年卷期：0
• ISSN：1549-960X

文摘

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.