Abstract
Rimegepant is a new medicine developed for the management of chronic headache due to migraine. This manuscript is an attempt to study the various structural, physical, and chemical properties of the molecules. The molecule was optimized using B3LYP functional with 6-311G + (2d,p) basis set. Excited state properties of the compound were studied using CAM-B3LYP functional with same basis sets using IEFPCM model in methanol for the implicit solvent atmosphere. The various electronic descriptors helped to identify the reactivity behavior and stability. The compound is found to possess good nonlinear optical properties in the gas phase. The various intramolecular electronic delocalizations and non-covalent interactions were analyzed and explained. As the compound contain several heterocyclic nitrogen atoms, they have potential proton abstraction features, which was analyzed energetically. The most important result from this study is from the molecular docking analysis which indicates that rimegepant binds irreversibly with three established SARS-CoV-2 proteins with ID 6LU7, 6M03, and 6W63 with docking scores − 9.2988, − 8.3629, and − 9.5421 kcal/mol respectively. Further assessment of docked complexes with molecular dynamics simulations revealed that hydrophobic interactions, water bridges, and π–π interactions play a significant role in stabilizing the ligand within the binding region of respective proteins. MMGBSA-free energies further demonstrated that rimegepant is more stable when complexed with 6LU7 among the selected PDB models. As the pharmacology and pharmacokinetics of this molecule are already established, rimegepant can be considered as an ideal candidate with potential for use in the treatment of COVID patients after clinical studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00894-021-04885-z.
Highlights
Migraine is one of the major chronic disease affecting a large number of people throughout the globe [1]
Rimegepant molecule structure was optimized by using density functional theory DFT-B3LYP as a method, and 6-311G + (2d,p) as a basis set
nature bonding orbital (NBO) studies revealed the intensity of various intramolecular interactions
Summary
Migraine is one of the major chronic disease affecting a large number of people throughout the globe [1]. Migraine reduces the quality of life and productivity, and limits the individual’s participation in the social setup [2]. The calcitonin gene-related peptide (CGRP) receptor was found to have a typical role in the onset of migraine and small drug molecules and antibodies are developed to antagonize this receptor [4, 5]. Humanized antibodies against CGRP or its receptor are being used as a prophylaxis measure in the management of migraine [6]. Rimegepant was developed as a CGRP receptor by using Heck reaction, and Hayashi–Miyaura and Ellman reactions [7].
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