Investigation of the binding pocket of human hematopoietic prostaglandin (PG) D2 synthase (hH-PGDS): A tale of two waters

The Influence of Bioisosteres in Drug Design: Tactical Applications to Address Developability Problems

“…One of the difficulties associated with displacing bound water molecules is illustrated by observations with a series of human prostaglandin D2 synthase (hH-PGDS) inhibitors based on the prototype 79 , IC 50 = 2.34 nM [ 120 ]. In the X-ray co-crystallographic structure of 79 with the enzyme, the isoquinoline nitrogen was observed to engage the hydrogen atom of a water molecule that interacted with Thr 159 and Leu 199 of hH-PGDS, leading to a study of the effect of incorporation of structural elements designed to displace the bridging water.…”

“…The hydroxymethylated naphthalene derivative 80 and its amine analogue 81 were synthesized and confirmed by X-ray studies to perform as anticipated, displacing the water molecule and directly engaging Thr 159 and Leu 199 with the full complement of interactions. However, the potency of these compounds was significantly diminished compared to 79 with IC 50 s of 1,480 nM for 80 and 845 nM for 81 , representing 360- and 630-fold differences, respectively [ 120 ]. A potential explanation was suggested based on a closer analysis of the crystal structures which revealed that the topographical disposition of the hydroxyl and amino moieties of 80 and 81 was close to the plane of the naphthalene ring (21° and 27°, respectively), an energetically unfavorable arrangement that incurs allylic 1,3 strain [ 10 , 122 ].…”

“…A potential explanation was suggested based on a closer analysis of the crystal structures which revealed that the topographical disposition of the hydroxyl and amino moieties of 80 and 81 was close to the plane of the naphthalene ring (21° and 27°, respectively), an energetically unfavorable arrangement that incurs allylic 1,3 strain [ 10 , 122 ]. In addition, the dihedral angle between the phenyl and naphthalene rings was ~20° less than the 117° observed for 79 , data that taken together suggested that the increased energy associated with the imposed conformational constraints outweighed the entropic gains associated with displacing the water molecule [ 120 ]. …”

X-ray structure of Fasciola hepatica Sigma class glutathione transferase 1 reveals a disulfide bond to support stability in gastro-intestinal environment

“…FhGST-S1 superposes to this enzyme with an RMSD of 1.91 Å over 192 Cα atoms. Interestingly, with respect to selectivity and potential drug development, FhGST-S1 demonstrated a different inhibition profile to hGSTS1–1 (PGDS) when probed with a series of isoquinolyl inhibitors that were synthesised as previously described 24 (Supplementary Table 1).…”

Open challenges in structure-based virtual screening: Receptor modeling, target flexibility consideration and active site water molecules description

“…Water displacement might, in fact, have unpredictable consequences on ligand binding affinity, as well as on ligand physicochemical properties, pharmacokinetics, specificity and safety [255]. In many cases, as previously reported, replacing tightly bound bridging waters only resulted in a slight improvement in the binding energy [244,[256][257][258], or even in a loss of binding affinity [259]. Overall, promoting enthalpic with respect to pre-supposed entropic gain could represent the winning strategy.…”