Pharmacophore modeling and conformational analysis in the gas phase and in aqueous solution of regioisomeric melatonin analogs. A theoretical and experimental study

• Published in: Journal of molecular structure 2017-04, Vol.1133, p.534-545
• Main Authors: Mendoza-Figueroa, Humberto, Martínez-Gudiño, Gelacio, Villanueva-Luna, Jorge E., Trujillo-Serrato, Joel J., Morales-Ríos, Martha S.
• Format: Article
• Language: English
• Subjects: 2-(N-acylaminoalkyl)indoles; Continuum solvent; Gas-phase; Pharmacophore modeling; Synthesis; Virtual screening
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2016.12.040

In this work, 2-(N-acylaminoalkyl)indoles 1a–1d, that incorporate a pMeOBn group at the 3-position of the indole ring were virtual screened as potential melatoninergic ligands by analog-based design study using pharmacophore modeling. Pharmacophore models for melatoninergic agonist and antagonist activity were developed in order to identify the molecular constraints that define the geometric relationship among chemical features in each model. The best hypothesis consisted of six features for agonists and eight features for antagonists. The models suggest that the agonists and antagonists can share the same 3D arrangement for the six common pharmacophoric elements identified: two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), one hydrophobic area (H), and two aromatic rings (AR). The extra hydrofobic interaction might be used as criterion for identified the pharmacological antagonist profile. Based on the pharmacophore fit, it was found that structures 1c and 1d show a good structural overlay that meets the requirements for the antagonistic pharmacophore hypothesis. Molecular modeling studies using the PCM solvation model predicted that the most stable conformers of 1a–1d match the antagonist pharmacophore hypothesis in contrast to those in the gas phase. Structures 1a–1c were synthesized only but the activities were not tested. [Display omitted] •New 2-(N-acylaminoalkyl)indoles have been synthesized and characterized.•Optimized geometry and theoretical calculations have been computed using DFT methods.•Conformational dependence in the gas phase and in aqueous solution has been investigated.•Pharmacophoric properties indicate their ability as antagonist melatoninergic ligands.