Crystal Structure-Based Virtual Screening for Fragment-like Ligands of the Human Histamine H₁ Receptor

Abstract

The recent crystal structure determinations of druggable class A G protein-coupled receptors (GPCRs) has opened up excellent opportunities in structure-based ligand discovery for this pharmaceutically important protein family. We have developed and validated a customized structure-based virtual fragment screening method against the recently determined human histamine H1 receptor (H1R) crystal structure. The method combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≤ 22 heavy atoms) H1R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 μM to 6 nM. The current study shows the potential of in silico screening against GPCR crystal structures to explore novel, fragment-like GPCR ligand space.

Sirtuin 5: a review of structure, known inhibitors and clues for developing new inhibitors

“…The second step is to use molecular docking to search possible binding poses for the established focused chemical library. The third step is to use interaction fingerprints-based methods or pharmacophore-based to filter the docking poses (de Graaf et al, 2011;Muthas et al, 2008). The final step is to use rescoring methods for example molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) (Suri and Naik, 2015) and ID-Score to predict the binding affinity for providing information to help select potential hit compounds.…”

Structure-based discovery and binding site analysis of histamine receptor ligands

“…One of the first published virtual fragment screening has been performed on the X-ray structure of the human histamine H1 receptor [23]. A fragment-like subset of ZINC database containing compounds with a formal charge of +1 (108,790 fragments) were docked to the binding pocket of hH1R by PLANTS.…”

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“…Moreover, the EF1% value of the validated protocol constructed here is significantly higher than the average value (17.3) resulted from the first SBVS campaign of 40 targets employing DUD and can therefore be considered as acceptable [10]. The validated protocol was subsequently employed to virtually screen eugenol (compound 1), its analogues (compounds 2-7) and their dimers (8)(9)(10)(11)(12)(13)(14). None of the compounds show better docking score as compared to the threshold compound of the EF1% value.…”

“…Tamoxifen itself is a prodrug that is metabolized in the liver results in some active metabolites (e.g., 4-hydroxytamoxifen and N-desmethyl-4-hydroxy-tamoxifen), with 30-100 fold activity in the binding to ER compared to its original form [6]. On the other hand, compared to tamoxifen and its metabolites, eugenol can be considered as a small fragment that has a potency to be developed further in a direction guided by a computer-aided structure-based design [7,8] to have compounds that have similar or even better affinities to ER than tamoxifen and its metabolites.…”