TY - JOUR

T1 - Structural insights into serotonin receptor ligands polypharmacology

AU - Podlewska, Sabina

AU - Kafel, Rafał

AU - Lacivita, Enza

AU - Satała, Grzegorz

AU - Kooistra, Albert J.

AU - Vass, Márton

AU - de Graaf, Chris

AU - Leopoldo, Marcello

AU - Bojarski, Andrzej J.

AU - Mordalski, Stefan

PY - 2018/5/10

Y1 - 2018/5/10

N2 - Identifying desired interactions with a target receptor is often the first step when designing new active compounds. However, attention should also be focused on contacts with other proteins that result in either selective or polypharmacological compounds. Here, the search for the structural determinants of selectivity between selected serotonin receptor subtypes was carried out. Special attention was focused on 5-HT7R and the cross-interactions between its ligands and the 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT2BR, and 5-HT6R subtypes. Selective and non-selective compounds for each pair of 5-HT7/5-HTx receptors were docked to the respective 5-HTR homology models and 5-HT1B/5-HT2BR crystal structures. The contacts present in the ligand-receptor complexes obtained by docking were characterized by the structural interaction fingerprint and statistically analyzed in terms of their frequency. The results allowed for the identification of amino acids that discriminate between selective and non-selective compounds for each 5-HT7/5-HTx receptor pair, which was further compared with available mutagenesis data. Interaction pattern characteristics for compounds with particular activity profiles can constitute the basis for the coherent selectivity theory within a considered set of proteins, supporting the ongoing development of new ligands targeting these receptors. The in silico results were used to analyze prospective virtual screening results towards the 5-HT7 receptor in which compounds of different chemotypes to known 5-HT7R ligands, with micromolar level activities were identified. The findings in this study not only confirm the legitimacy of the approach but also constitute a great starting point for further studies on 5-HT7R ligands selectivity.

AB - Identifying desired interactions with a target receptor is often the first step when designing new active compounds. However, attention should also be focused on contacts with other proteins that result in either selective or polypharmacological compounds. Here, the search for the structural determinants of selectivity between selected serotonin receptor subtypes was carried out. Special attention was focused on 5-HT7R and the cross-interactions between its ligands and the 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT2BR, and 5-HT6R subtypes. Selective and non-selective compounds for each pair of 5-HT7/5-HTx receptors were docked to the respective 5-HTR homology models and 5-HT1B/5-HT2BR crystal structures. The contacts present in the ligand-receptor complexes obtained by docking were characterized by the structural interaction fingerprint and statistically analyzed in terms of their frequency. The results allowed for the identification of amino acids that discriminate between selective and non-selective compounds for each 5-HT7/5-HTx receptor pair, which was further compared with available mutagenesis data. Interaction pattern characteristics for compounds with particular activity profiles can constitute the basis for the coherent selectivity theory within a considered set of proteins, supporting the ongoing development of new ligands targeting these receptors. The in silico results were used to analyze prospective virtual screening results towards the 5-HT7 receptor in which compounds of different chemotypes to known 5-HT7R ligands, with micromolar level activities were identified. The findings in this study not only confirm the legitimacy of the approach but also constitute a great starting point for further studies on 5-HT7R ligands selectivity.

KW - Selectivity

KW - Serotonin receptor 5-HT

KW - Structural interaction fingerprint

KW - Virtual screening

UR - http://www.scopus.com/inward/record.url?scp=85045693396&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2018.04.010

DO - 10.1016/j.ejmech.2018.04.010

M3 - Journal article

C2 - 29679900

AN - SCOPUS:85045693396

VL - 151

SP - 797

EP - 814

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -