Hybrid approach to structure modeling of the histamine H3 receptor: Multi-level assessment as a tool for model verification

Abstract

The crucial role of G-protein coupled receptors and the significant achievements associated with a better understanding of the spatial structure of known receptors in this family encouraged us to undertake a study on the histamine H3 receptor, whose crystal structure is still unresolved. The latest literature data and availability of different software enabled us to build homology models of higher accuracy than previously published ones. The new models are expected to be closer to crystal structures; and therefore, they are much more helpful in the design of potential ligands. In this article, we describe the generation of homology models with the use of diverse tools and a hybrid assessment. Our study incorporates a hybrid assessment connecting knowledge-based scoring algorithms with a two-step ligand-based docking procedure. Knowledge-based scoring employs probability theory for global energy minimum determination based on information about native amino acid conformation from a dataset of experimentally determined protein structures. For a two-step docking procedure two programs were applied: GOLD was used in the first step and Glide in the second. Hybrid approaches offer advantages by combining various theoretical methods in one modeling algorithm. The biggest advantage of hybrid methods is their intrinsic ability to self-update and self-refine when additional structural data are acquired. Moreover, the diversity of computational methods and structural data used in hybrid approaches for structure prediction limit inaccuracies resulting from theoretical approximations or fuzziness of experimental data. The results of docking to the new H3 receptor model allowed us to analyze ligand—receptor interactions for reference compounds.

Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery

“…Jonczyk et al [ 80 ] generated H 3 R homology models and used a hybrid assessment of these models based on knowledge-based scoring algorithm and two-step docking protocols including GOLD and Glide. The models also passed the quality analysis performed using BCL::Score, QMEAN and PSVS methods.…”

“…Thioperamide spans horizontally between two negatively charged residues D 3.32 and E 5.46 and the ligand is embedded in a pocket between helices TM3, TM5 and TM6 [ 58 , 59 ]. However, in a study [ 80 ] based on another template, M3 muscarinic receptor, thioperamide was docked vertically and interacted only with D 3.32 . There are two negatively charged residues, D 3.32 and E 5.46 , in the orthosteric ligand binding pocket of hH 3 R (similarly to hH 4 R).…”

“…The second acidic binding point is created by E 5.46 and adjacent tyrosine Y 6.51 . In a study by Jonczyk et al [ 80 ], a series of amine antagonists including JNJ5207852 was docked to hH 3 R in vertical poses, and the protonated amines of these ligands were bound to E 5.46 , Y 3.33 and Y 6.51 . It was also found that antagonist clobenpropit with protonated imidazole ring and isothiourea fragments, used both acidic points, D 3.32 and E 5.46 , in the ligand binding space: imidazole interacted with D 3.32 while isothiourea group, as a second protonated system, created a salt bridge with E 5.46 .…”

A complex view of GPCR signal transduction: Molecular dynamics of the histamine H3 membrane receptor

“…Thus, based on the crystals of rhodopsin, 26 3D in silico models for H3R have been obtained in the past. 20,23,[27][28][29][30][31][32][33][34][35][36][37] Nevertheless, these models suffer from a variety of imperfections during their building, such as use of incorrect or absent alignments; manual adjustments and manipulations; energy refinement in vacuo; short molecular dynamics (MD) trajectories (1-10 ns); non consideration of the state of the template structure (active/inactive). Other models do not contain any ligands.…”

Pharmacological andSARanalysis of theLINS01 compounds at the human histamine H1, H2, and H3receptors

“…Several H 3 R ligands reported in the literature present the N ‐arylpiperazine moiety such as DL‐80 which presents medium to low affinity to H 3 R, but with certain selectivity over H 4 R. However, these compounds present a longer linker than the LINS01 compounds, and thus, the position of the most basic nitrogen changes accordingly. Docking studies suggest that a salt bridge between a basic nitrogen and Glu206 is a key interaction to the antagonist activity. Figure shows the proposed interactions of several antagonists with H 3 R and the hypothetical interaction of 1 .…”