Construction and validation of pharmacophore model of calcitonin gene-related peptide receptor antagonists using ligand- and structure-based approaches

Abstract

Context

Calcitonin gene-related peptide (CGRP) is a valid target for migraine disorder. Antagonizing the CGRP receptor elicits beneficial effects in migraine, although several CGRP receptor antagonists are currently available in clinical practice, a well-defined pharmacophore model has not yet been proposed. Particularly appropriate distances between the pharmacophoric elements are not reported. Therefore, a three-point pharmacophore model was constructed based on the common structural features present in the clinically available CGRP receptor antagonists. To evaluate the proposed pharmacophore elements and model, their presence is mapped onto the reported molecules, and the distances between the elements are measured. A total of 27 molecules is shortlisted based on CGRP receptor antagonistic potency. Among them, 21 molecules possessed the proposed pharmacophore elements, and in the remaining 6 molecules, only one pharmacophore element was not matched with the proposed model. The distances between the pharmacophore elements were measured; among the 21 molecules, only five molecules (3, HTL0022562, BMS-694153, 19, and BMS-846372) possessed slight to moderate deviations. Based on the proposed pharmacophore model, new molecules (T1-T5) were designed as CGRP receptor antagonists. To validate the proposed model, the clinically existing and designed molecules were docked into the active site of the CGRP receptor. In the designed molecules, T3 (-10.3 kcal/mol) followed by T5 (-9.8 kcal/mol) exhibited binding affinity. Though the docking score of these novel molecules is less as compared to standard molecules: 6ZHO-lig (-13.6 kcal/mol) and as Zavegepant (-11.3 kcal/mol). These molecules exhibit the common interactions (H-bonding with Thr2122 and pi-pi with Trp2121) as standard molecules. During MDS studies till 500 ns, standard molecules: 6ZHO-lig and Zavegepant followed the docking results of higher binding affinity as compared to novel designed molecules T3 and T5. However, different MDS parameters exhibited satisfactory stability of these molecules into the active site of CGRP. The T3 and T5 molecules displayed satisfactory pharmacokinetic properties in the SwissADME prediction tool. Further, optimization of these early-stage hits is required to improve the binding affinity and ADME profile. The ligand- and structure-based approaches support the reliability of the proposed pharmacophore model. In conclusion, the constructed pharmacophore model will serve as a template for the design of new molecules as CGRP receptor antagonists.

Methods

The most common structural features of clinically available CGRP receptor antagonists were considered as pharmacophoric elements of CGRP receptor antagonists. Using ACDLABS-2021 2.1/3D Viewer (CHARMM parameterization) software, the distances between pharmacophore elements were measured. The designed molecules were tested for binding mode analysis using molecular docking studies in the AutoDock Vina tool. The best docked molecules were further tested for stability studies using the Desmond tool. For pharmacokinetic studies, the SwissADME tool was used.