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.

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

“…Reports in the literature have showed how differential displacement of water molecules can lead to selective ligands [25][26][27][28][29][30] . The rationale behind the engineering or enhancing of the selectivity of a ligand for similar proteins directly follows from the displacement energetics: if the displacement of one or more water molecules from protein "A" carries a small free energy penalty, but the displacement from protein "B" carries a large penalty, then the difference in the displacement free energies will result in the ligand binding with higher affinity to protein "A" than protein "B".…”

A Water-Bridged Cysteine-Cysteine Redox Regulation Mechanism in Bacterial Protein Tyrosine Phosphatases

“…We used the program WaterMap, 35 , 36 which combines a short (2 ns) MD simulation with solvent clustering and thermodynamic analysis by using inhomogeneous solvation theory. 37 , 38 This approach has been used to characterize the energetics of water molecules at the surface of proteins 39 and explain selectivity between highly related protein binding sites, 40 , 41 , 42 binding kinetics, 43 and the role of water networks in entropy and/or enthalpy compensation. 44 , 45 Cys53 is predicted to have little tightly bound water structure around it, in line with its higher reactivity.…”

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland

“…In all cases, they considered the presence of molecules of water in the binding pocket of the proteins. They either started with a known inhibitor of the protein or through a fragment‐based screening approach in order to develop better inhibitors, using Watermap as the main tool . The third and closing lecture of the conference was given by Dr. Klemens Högenauer (Novartis) about PI3K inhibitors.…”

“…They either started with ak nown inhibitor of the protein or through af ragmentbased screening approach in order to develop better inhibitors, using Watermap ast he main tool. [17,18] The third and closing lecture of the conference was given by Dr.K lemens Hçgenauer (Novartis) about PI3Ki nhibitors. By rearranging fragmentso fk nown oncologicdrugs, his team improved the selectivity and potency of the compound toward other PI3Ks.…”