A Structural View on Druggability

Egner, Ursula; Hillig, R.C.

doi:10.1002/9781118681121.ch2

Cited by 1 publication

(2 citation statements)

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“…In this context, the effort spent in disclosing the relevant physicochemical features that determine the binding site druggability is not surprising. − While no single physicochemical parameter consistently dominates the signature of binding pockets, these studies have revealed that the druggability is substantially modulated by descriptors of pocket shape, such as volume, depth and enclosure, and hydrophobicity, whereas polar or charged residues may be more relevant by imparting specificity, or by conferring structural stability to the ligand-bound complex through kinetic trapping. The knowledge gained from these studies has significant implications in key aspects of structure-based drug discovery, such as target assessment and validation − and predicting the maximal affinity that a drug-like molecule may attain for a given binding site. − …”

Section: Introductionmentioning

confidence: 99%

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Screening and Biological Evaluation of Soluble Epoxide Hydrolase Inhibitors: Assessing the Role of Hydrophobicity in the Pharmacophore-Guided Search of Novel Hits

Vázquez¹,

Ginex²,

Herrero³

et al. 2023

J. Chem. Inf. Model.

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The human soluble epoxide hydrolase (sEH) is a bifunctional enzyme that modulates the levels of regulatory epoxy lipids. The hydrolase activity is carried out by a catalytic triad located at the center of a wide L-shaped binding site, which contains two hydrophobic subpockets at both sides. On the basis of these structural features, it can be assumed that desolvation is a major factor in determining the maximal achievable affinity that can be attained for this pocket. Accordingly, hydrophobic descriptors may be better suited to the search of novel hits targeting this enzyme. This study examines the suitability of quantum mechanically derived hydrophobic descriptors in the discovery of novel sEH inhibitors. To this end, three-dimensional quantitative structure−activity relationship (3D-QSAR) pharmacophores were generated by combining electrostatic and steric or alternatively hydrophobic and hydrogen-bond parameters in conjunction with a tailored list of 76 known sEH inhibitors. The pharmacophore models were then validated by using two external sets chosen (i) to rank the potency of four distinct series of compounds and (ii) to discriminate actives from decoys, using in both cases datasets taken from the literature. Finally, a prospective study was performed including a virtual screening of two chemical libraries to identify new potential hits, which were subsequently experimentally tested for their inhibitory activity on human, rat, and mouse sEH. The use of hydrophobic-based descriptors led to the identification of six compounds as inhibitors of the human enzyme with IC 50 < 20 nM, including two with IC 50 values of 0.4 and 0.7 nM. The results support the use of hydrophobic descriptors as a valuable tool in the search of novel scaffolds that encode a proper hydrophilic/hydrophobic distribution complementary to the target's binding site.

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Section: Introductionmentioning

confidence: 99%

“…The knowledge gained from these studies has significant implications in key aspects of structure-based drug discovery, such as target assessment and validation 11 − 15 and predicting the maximal affinity that a drug-like molecule may attain for a given binding site. 16 − 19 …”

Section: Introductionmentioning

confidence: 99%