The 5-HT_1A Agonism Potential of Substituted Piperazine-Ethyl-Amide Derivatives Is Conserved in the Hexyl Homologues: Molecular Modeling and Pharmacological Evaluation

Abstract

In a series of carboxamide and sulphonamide alkyl (ethyl to hexyl) piperazine analogues, although the size of the linker is very different, ethyl and hexyl derivatives possess a high affinity for 5-HT(1A) receptors. Docking studies clearly show that hexyl and ethyl compounds favorably interact with the binding site of the active conformation of 5-HT(1A) receptors, thus confirming a possible agonist profile. This activity is effectively detected in electrophysiological experiments in which all four compounds inhibit the activity of rat dorsal raphe serotonergic neurons.

Synthesis and Docking of Novel 3‐Indolylpropyl Derivatives as New Polypharmacological Agents Displaying Affinity for 5‐HT1AR/SERT

“…Docking experiments showed that the two most potent compounds of this series at the 5-HT 1A receptor (11b and 11d) exhibited a binding mode in which the main contact was the well-described coulombic interaction between a protonated nitrogen atom of the piperazine ring and Asp116 [8,9,20,21]. Interestingly, in the case of compounds 11a and 11c, this interaction was absent, which agrees with the lower affinity exhibited by these derivatives (Fig.…”

Latest developments in molecular docking: 2010–2011 in review

“…[45,47,150,151] Homology models were used for docking into neuronal nicotinic receptor, [152] Trypanosoma brucei phosphodiesterases, [153] prostaglandin E synthase 1, [154] aryl hydrocarbon receptor transcription factor, [155] as well as VS against the following: the s1 receptor, [156] calpain, [157] kinases, [158][159][160][161] and GPCRs. [45,47,126,151,[162][163][164][165] Structural validation studies For us to have an expectation that a given docking setup (i.e., choice of program, scoring function, and approaches to deal with ligand and receptor flexibility) will deliver reliable results, it must be validated for a system under investigation (i.e., ligand and receptor type). It is critical that users assess their unique docking setup(s) prior to embarking on a docking project: either by searching the literature (to check whether such validation has already been performed) or by performing it, if necessary.…”

“…The GPCR modeling and docking studies dealt with a variety of issues: validation of Prime homology models by VS with Glide (nine publicly accessible models: dopamine (D 2 , D 3 , and D 4 ), serotonin (5-HT 1B , 5-HT 2A , 5-HT 2B , and 5-HT 2C ), histamine (H 1 ), and muscarinic (M 1 ) receptors); [47] use of ensemble of alternative receptor conformations to account for its flexibility; [46] fragment screening by PLANTS (histamine H 1 receptor); [126] receptor subtype selectivity with DarwinDock (H 3 versus H 1 , H 2 , and H 4 receptors) [163] and ICM (adenosine receptors A 1 , A 2A , A 2B , and A 3 ). [48] agonist profiling (serotonin 5-HT 1A receptor); [164] design of novel ligands for adenosine A 2A [171,172] and dopamine D 3 . [173] receptors; development of universal active probes; [162] a comparison of Glide, Gold, and ICM-Pro for docking into the homology model of the 5-HT 2A receptor; [165] and peptide docking with photoaffinity labeling constraints in ICM-Pro.…”

Molecular Docking an Enchanted Way in The Discovery of Novel Molecule in Designing Drug: A Focused Review

“…Crystal structure was subjected to protein preparation wizard for filling missing loops and side chains (using Prime), ionization, H-bond optimization, heterogeneous state generation, protonation and overall minimization. All other ligands, water and ions were removed except ATP molecule [46][47][48][49]. Grid file for docking was constructed considering ATP molecule as centroid of grid box of 10 ֩ A size [50][51].…”