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

Abstract

Obesity prevalence continues to be a foremost health concern across the globe leading to the development of major health risk conditions like type II diabetes, hyperlipidemia, hypertension and even cancers. Because of the deprived drug-based management system, there is an urgent need for the development of new drugs aiming at satiety and appetite control targets. Among the reported satiety signaling targets, 5HT2C receptor plays a crucial role in decreasing appetite and has become a promising target for the development of anti-obesity drugs. Lorcaserin, a 5HT2C receptor agonist and the only drug available in the market, was designed based on the receptor mechanism of action. Due to limited drug options available and considering the adverse drug effects of Lorcaserin, the development of new drugs which are highly specific toward the 5HT2C target and with lesser side effects is essential. The present study is majorly focused on developing new 5HT2C agonists through computational approaches like screening, docking, and simulation using Phase, QikProp, Glide and Desmond applications of the Schrodinger suite. Screening protocols resulted in eight best hit molecules with affinity for the receptor and among them, five hits displayed binding affinity toward the conserved residue Asp 134 of the receptor. The stability of the five molecules in complex with the 5HT2C receptor was studied through molecular dynamic simulations. Three molecules, ZINC32123870, ZINC40312983 and ZINC32124535, maintained stable interactions with the Asp 134 residue throughout the 50 ns simulation run time. Further, due to the high sequence similarity seen among the receptors of 5HT2 family, the three potential hits were cross validated against other subtypes 5HT2A and 5HT2B of the 5HT2 family to determine the specificity of the molecules against the target. Among the three hits, ZINC32124535 was identified as the best potential hit based on the hydrogen bond interaction percentage with Asp residue [5HT2A (Asp 155:60%); 5HT2B (Asp155: No interaction); 5HT2C (Asp 134:86%)]. The ZINC32124535 molecule produced one salt bridge and hydrogen bond interactions with Asp 134, alike the known drug Lorcaserin. Based on the results, ZINC32124535 was identified as the best potential hit against the 5HT2C receptor.

Structural and simulation analysis of hotspot residues interactions of SARS-CoV 2 with human ACE2 receptor

“…Second step in the simulations protocol was minimization, the complex obtained from the system builder was relaxed by setting the maximum iterations number to 2000 and remaining parameters were set to default. Finally, the minimized complex was subjected to molecular dynamic simulations by setting the ensemble parameter to NPT [isothermal-isobaric ensemble, Number of particles (N), Pressure (P) and Temperature (T)], 300 K temperature, 1 bar pressure, simulation run time was set to 100 ns (Islam et al, 2020) and relaxed using the default relation protocol (Guo et al, 2010;Veeramachaneni et al, 2019).…”

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

“…For the other presently proposed agonist, c49, inspection of the contacts indicates that there are 26 residues within 6 Ang of the ligand, also with a combination of nonpolar, polar and acidic residues. Within the active site (Figure 2b), c49 maintained a number of interactions which are similar to those of c34, described above, as well as those of lorcaserin [15]. These interactions include the key conserved residue Asp 134 and Phe 214, Phe 327 and Phe 328, as well as a cluster of surrounding nonpolar sidechains within the binding pocket, including Ile 131, Val 135, Val 208 and Leu 209.…”

“…The combination of an additional interaction with Glu 347 and possible hydrogen bonding with Tyr 118 suggests that c34 may be capable of acting as a more potent agonist than LOR and other For c34, inspection of the contacts indicates that there are 17 residues within 4 Å distance of the ligand, with a combination of nonpolar, polar and acidic residues. 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].…”

“…Although research has shown that CS possesses anti-hyperlipidemia properties [14], the potential effect of CS on appetite suppression has not been investigated. 5-HT2C receptor, a subtype of serotonin receptors, plays an important role in reducing appetite [15,16]. Lorcaserin (LOR), a current anti-obesity drug, is a highly selective 5-HT2C receptor agonist acting as an appetite depressant [17][18][19].…”

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

“…To this end, first of all, using the PubMed database [ 69 ], we characterized each of the 42 hippocampal DEGs (of tame versus aggressive rats) identified in this work ( Table 2 ), in terms of how downregulation or upregulation of their orthologous human genes can manifest itself in hypertension, as presented [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ,…”