The Importance of Hydration Thermodynamics in Fragment‐to‐Lead Optimization

Abstract

Using a computational approach to assess changes in solvation thermodynamics upon ligand binding, we investigated the effects of water molecules on the binding energetics of over 20 fragment hits and their corresponding optimized lead compounds. Binding activity and X-ray crystallographic data of published fragment-to-lead optimization studies from various therapeutically relevant targets were studied. The analysis reveals a distinct difference between the thermodynamic profile of water molecules displaced by fragment hits and those displaced by the corresponding optimized lead compounds. Specifically, fragment hits tend to displace water molecules with notably unfavorable excess entropies-configurationally constrained water molecules-relative to those displaced by the newly added moieties of the lead compound during the course of fragment-to-lead optimization. Herein we describe the details of this analysis with the goal of providing practical guidelines for exploiting thermodynamic signatures of binding site water molecules in the context of fragment-to-lead optimization.

Computer-aided drug design: time to play with novel chemical matter

“…The inclusion of small organic molecules in the solvent that are used as probes (MD simulations with mixed cosolvents, or MDmix) was initially devised as a binding site identification and druggability prediction method [20,21], but is finding numerous applications, including prediction of pharmacophoric points, detection of cryptic pockets, or ligand scoring [22]. MD simulations, with or without cosolvents, also allow unprecedented characterization of the hydration preferences of binding sites, a fundamental property for ligand design [23]. When the aim is to study particular ligands, throughput is an important consideration.…”

The Structure ofN‐phenyl‐pyrazoles and Indazoles: Mononitro, Dinitro, and Trinitro Derivatives

“…Although some biological activities have been reported, none of the compounds have been developed as a drug: antibacterial (compound line 194 of Table ); anti‐inflammatory ; memory enhancement .…”

The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

“…Detailed thermodynamic and structural analyses of the water network and its perturbation by ligands can distinguish water molecules whose repulsion from the binding site is favorable or unfavorable in terms of their contribution to binding free energy and its components [22,23,24,25,26]. Although an assignment of free-energy and its components to water molecules is an approximation it contributes to our understanding of the role of water in ligand binding.…”

“…Next there are two options to improve the affinity of the fragment further. In one case a chlorine atom was introduced to the ortho position of the 2-methoxyphenyl ring (25) that was replaced by another methoxy group resulting the dimethoxyphenyl analogue (26). The other option replaces the methyl group of the aminopyrimidine ring by a chlorine (27) and the introduction of the second methoxy group yields the chloro analogue (28) of 26.…”