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.
Preparation of the C1-C10 Fragment of Carbonolide B. A Relay Approach to Carbomycin B. -The allofuranoside (I) reacts with magnesium compound (II) to give selectively the furanoside (III). It is elaborated to the C1-C10 fragment (IX) via hydroboration of the prochiral double bond of (III), oxidation cleavage between C5-C6 of the diol (V) and subsequent three-carbon elongation at the C5-position. -(SHIMURA, T.; KOMATSU, C.; MATSUMURA, M.; SHIMADA, Y.; OHTA, K.; MITSUNOBU, O.; Tetrahedron Lett. 38 (1997) 48, 8341-8344; Dep. Chem., Coll. Sci. Eng., Aoyama Gakuin Univ., Setagaya, Tokyo 157, Japan; EN)
1997 stereochemistry stereochemistry (general, optical resolution) O 0030
-037Pronounced Enhancement of Stereoselectivity in Asymmetric Hydrogenation of 2-Substituted 2-Propen-1-ols by Transient Acylation. -Aroylated allyl alcohols, e.g. (I), are hydrogenated with enhanced asymmetric induction compared with the corresponding free or benzylated allyl alcohols. Also in compounds such as (III) the benzoyl group has a beneficial effect in the discrimination of the π-face. -(SHIMIZU, H.; SHIMADA, Y.; TOMITA, A.; MITSUNOBU, O.; Tetrahedron Lett. 38 (1997) 5, 849-852; Dep. Chem., Coll. Sci. Eng., Aoyama Gakuin Univ., Setagayaku, Tokyo 157, Japan; EN)
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