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• W4378839367 abstract "The study intends to repurpose FDA drugs and investigate the mechanism of (5HT2BR) activation by comprehending inter-residue interactions. The 5HT2BR is a novel thread, and its role in reducing seizures in Dravet syndrome is emerging. The crystal structure (5HT2BR) is a chimera with mutations; hence 3D-structure is modeled (4IB4: 5HT2BRM). The structure is cross-validated to simulate the human receptor using enrichment analysis (ROC: 0.79) and SAVESv6.0. Virtual screening of 2456 approved drugs yielded the best hits that are subjected to MM/GBSA and molecular dynamic (MD) simulations. The 2 top drugs Cabergoline (−53.44 kcal/mol) and Methylergonovine (−40.42 kcal/mol), display strong binding affinity, and ADMET/SAR analysis also suggests their non-mutagenic or non-carcinogenic nature. Methylergonovine has a weaker binding affinity and lower potency than standards [Ergotamine (agonist) and Methysergide (antagonist)] due to its higher Ki (1.32 M) and Kd (6.44 ×10−8 M) values. Compared to standards, Cabergoline has moderate binding affinity and potency [Ki = 0.85 M and Kd = 5.53 × 10–8 M]. The top 2 drugs primarily interact with conserved residues (ASP135, LEU209, GLY221, ALA225, and THR140) as in agonists, unlike the antagonist. The top 2 drugs, upon binding to the 5HT2BRM, modify the helices VI, V, and III and shift the RMSD 2.48 Å and 3.07 Å. LEU209 forms a latch with residues 207–214 (forms a lid) in the 5HT2BRM receptor, which enhances agonist binding and prevents drug escape. Methylergonovine and Cabergoline interact more stongly with ALA225 than the antagonist. The post-MD analysis of Cabergoline suggests a better MM/GBSA value (−89.21 kcal/mol) than Methylergonovine (−63.54 kcal/mol). In this study, Cabergoline and Methylergonovine's agonistic mechanism and solid binding properties suggest their strong role in regulating the 5HT2BR and might target drug-resistant epilepsy." @default.
• W4378839367 created "2023-06-01" @default.
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• W4378839367 date "2023-08-01" @default.
• W4378839367 modified "2023-09-30" @default.
• W4378839367 title "Designing the 5HT2BR structure and its modulation as a therapeutic target for repurposing approach in drug-resistant epilepsy" @default.
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• W4378839367 doi "https://doi.org/10.1016/j.eplepsyres.2023.107168" @default.
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