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

Abstract

Introduction: Application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors. Areas covered: In this paper, we review the development of histamine receptors models and their application on drug discovery. Expert opinion: In our opinion, the application of atomistic histamine receptor models played a significant role in understanding key ligand-receptor interactions as well as in the discovery of novel chemical starting points. The recently solved H1 receptor structure is a major milestone in structure-based drug discovery, however our analysis also demonstrate that for building H3 and H4 receptor homology models other GPCRs may be more suitable as a template. For these receptors we envisage that the development of higher quality homology models will significantly contribute to the discovery and optimization of novel H3 and H4 ligands.

Ligand-guided homology modeling drives identification of novel histamine H3 receptor ligands

“…This binding mode agrees well with several previous docking studies of histamine [29,30]. Each of the 5 chosen binding poses is involved in an interaction with charged residues D 3.32 and E 5.46 , which is agreement with the common binding mode of aminergic GPCRs involving D 3.32 and with the importance of E 5.46 for proper ligand placement in our homology modeling approach (Fig 2) that is further supported by mutational data [28] and previous docking studies [29,30]. Docking poses of CHEMBL1923737, CHEMBL2151197 (Fig 3, model A and B) and CHEMBL1269844 (Fig D part A in S1 File) only interact with D 3.32 despite the already described importance of E 5.46 in ligand binding .…”

“…This conformation is also energetically unfavorable, since it is pointing toward the lipophilic membrane and no amino acid with opposite charge is present to compensate the negative charge. The importance of E 5.46 in ligand binding is in agreement with mutational studies [28] and was already described in previous homology modeling studies for H 3 R [29,30]. Another atom with a rather high difference in mean atom position (2.1 Å) is a distal side chain carbon of L 7.42 .…”

“…The preferred docking pose of the histamine analogue CHEMBL214312 (Fig D part B in S1 File) is complexed between D 3.32 and E 5.46 [35]. This binding mode agrees well with several previous docking studies of histamine [29,30]. Each of the 5 chosen binding poses is involved in an interaction with charged residues D 3.32 and E 5.46 , which is agreement with the common binding mode of aminergic GPCRs involving D 3.32 and with the importance of E 5.46 for proper ligand placement in our homology modeling approach (Fig 2) that is further supported by mutational data [28] and previous docking studies [29,30].…”

Structure-Based Virtual Screening for Ligands of G Protein–Coupled Receptors: What Can Molecular Docking Do for You?

“…Virtual screens have also been carried out using homology models of the other histamine receptor subtypes (Kiss et al, 2014;Vass et al, 2014b;Istyastono et al, 2015;Kiss and Keser} u, 2016;Schaller et al, 2019). Both Vass et al (2014b) and Istyastono et al (2015) used homology models of the H 4 R in virtual screening of fragment libraries.…”

Molecular Modelling of Potential Candidates for the Treatment of Depression

“…One of the main structural characteristics of H 3 receptor antagonists is the presence of at least one amino group . An important ionic interaction seems to take place between the amino group and a negatively charged amino acid residue in the H 3 receptor active site . In this sense, the GCOD (2,−7,−2,p−) would be related to the conformation adopted by the R substituent and its impact on the activity of the compounds.…”