Identification of natural products as novel ligands for the human 5-HT2C receptor

Abstract

G protein-coupled receptors (GPCRs) constitute the largest human protein family with over 800 members, which are implicated in many important medical conditions. Serotonin receptors belong to the aminergic GPCR subfamily and play important roles in physiological and psychological activities. Structural biology studies have revealed the structures of many GPCRs in atomic details and provide the basis for the identification and investigation of the potential ligands, which interact with and modulate the receptors. Here, an integrative approach combining a focused target-specific natural compound library, a thermal-shift-based screening method, affinity mass spectrometry, molecular docking, and in vitro as well as in vivo functional assay, was applied to identify (–)-crebanine and several other aporphine alkaloids as initial hits for a human serotonin receptor subtype, the 5-HT2C receptor. Further studies illuminated key features of their binding affinity, downstream signaling and tissue reaction, providing a molecular explanation for the interaction between (–)-crebanine and human 5-HT2C receptor.

Co-encapsulation of curcumin and doxorubicin in albumin nanoparticles blocks the adaptive treatment tolerance of cancer cells

“…In this study, we investigated the co-treatment of MCF-7 resistant breast cancer cells with Dox and the chemosensitizer curcumin (Cur). Cur is a natural compound that inhibits the MDR protein family-member P-glycoprotein (P-gp) and blocks the transport of anti-cancer drugs out of cancer cells (Hsieh et al 2014;Neerati et al 2013;Peng et al 2018;Sahu et al 2016;Umsumarng et al 2015;Vinod et al 2013;Wang et al 2016;Zhang et al 2016). Both the drugs were encapsulated into ANPs and co-administered to cells both sequentially and simultaneously.…”

Pharmacophore Directed Screening of Agonistic Natural Molecules Showing Affinity to 5HT2C Receptor

“…Receptor downloaded from protein databank was prepared using the protein preparation wizard to convert the raw structure into a refined structure [40,41]. Through a receptor grid generation step, the prepared protein active site was locked and docked with seven out of eight ligand compounds selected from the above steps.…”

“…The interaction of the highly conserved residue Asp 134 with molecules was considered the most important in performing agonist activity [27,39,41,42]. The other important amino acids in the vicinity region reported were Ser 138, Tyr 358, Tyr 324, and Arg 195 [43,44].…”

“…Molecular specificity against the target is more important to reduce adverse side effects. Specificity plays a crucial role in screening agonists targeting the 5HT 2C receptor because of the high sequence similarity of the conserved domains, as well as the overall sequence identity among the family members (55% with 5HT 2A and 58% with 5HT 2B receptors, respectively) [41]. The three best hits identified against 5HT 2C receptor, ZINC32123870, ZINC40312983, and ZINC32124535, were cross validated against other members of the family, 5HT 2A and 5HT 2B receptors, using the same protocol along with Lorcaserin.…”

Mechanisms of Action of Cassiae Semen for Weight Management: A Computational Molecular Docking Study of Serotonin Receptor 5-HT2C

“…Within the active site (Figure 2a), c34 maintained a number of interactions which are similar to those of lorcaserin [15]. There is a close contact with the highly-conserved Asp 134, for which it is known that its involvement is vital to agonist activity [23][24][25][26]. There are also contacts with a number of phenylalanine residues, including Phe 214, Phe 327 and Phe 328, some of which are mediated via π-π ring-stacking interactions with the polycyclic aromatic rings of c34.…”