Study of the structural features and solvent effects using ab initio molecular dynamics and energy decomposition analysis of atogepant in water and ammonia

Abstract

Atogepant is a new drug developed for treating migraine in adults, marking it active with a calcitonin gene-related peptide (CGRP) receptor antagonist, which can be used to prevent migraine. The main objective of this manuscript is to study the structure and interaction of atogepant with solvents like water and ammonia. We optimized the molecule using the DFT method and did the conformational analysis. A potential energy scan was conducted to ascertain the conformation preference of the compound and found that global minima are at the angles 60, 180, and 300 0 with respect to the C30-C38 bond. The electronic spectra were produced using RCAM-B3LYP functional and identical basis sets with different polar and nonpolar solvents. Methanol showed excellent solvation energy –33.5448 kcal/mol and more interactions in implicit studies. Qualitative studies indicated that the compound has more non-covalent interactions with water when compared to ammonia. Local energy decomposition analysis using DLPNO/CCSD(T) level revealed the exact type of interaction between the drug and water/ammonia. Later we studied the interaction between the molecule and explicit solvent molecules using ab initio molecular dynamics simulations and found that the drift velocity is more complex with water. Physico-chemical properties like reactive sites, bioactivities, stabilities, solvation energy, occupancies of electrons in atomic and bonding orbitals, different types of hydrogen bonds, the steric force of interactions, delocalization of electrons, and reactive sites of nucleophiles, and electrophiles are also reported.