The binding mechanism of Covalent Organic Frameworks (COFs) to Calcitonin Gene-Related Peptide Receptors (CGRPRs)

Calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein type 1 (RAMP1) are key components of the calcitonin gene-related peptide (CGRP) receptor, which is upregulated during migraine attacks, contributing to enhanced CGRP signaling. This study aimed to investigate the binding of covalent organic framework (COFs) models to CLR/RAMP1 at the molecular level using molecular dynamics (MD) and docking simulations. To assess the efficacy and inhibitory effects of COF structures on the CLR/RAMP1 complex, two antimigraine drugs, ubrogepant and rimegepant, were used as controls. These findings substantiate the pronounced affinity of the TPE-COF, 3D-Py-COF, and 4PE-1P-COF models for interacting with CGRP, impeding its function and attenuating pain. This study demonstrates that COFs can function as direct macromolecular antagonists of the CLR/RAMP1 complex, repositioning COFs from passive nanocarriers to direct macromolecular antagonists. Unlike prior work focused on COF-mediated drug encapsulation/release, we computationally validate that specific COFs inherently exhibit bioactive potential against CGRPR. However, further investigation is necessary to explore a broad range of COF structures that can be investigated initially at the molecular and mathematical scales. Thereafter, the selected COFs may undergo further evaluation, such as laboratory feasibility tests, in vitro or in vivo studies.