title: Quantitative structure-activity relationships and docking studies of calcitonin gene-related peptide antagonists.
abstract: Defining the role of calcitonin gene-related peptide in migraine pathogenesis could lead to the application of calcitonin gene-related peptide antagonists as novel migraine therapeutics. In this work, quantitative structure-activity relationship modeling of biological activities of a large range of calcitonin gene-related peptide antagonists was performed using a panel of physicochemical descriptors. The computational studies evaluated different variable selection techniques and demonstrated shuffling stepwise multiple linear regression to be superior over genetic algorithm-multiple linear regression. The linear quantitative structure-activity relationship model revealed better statistical parameters of cross-validation in comparison with the non-linear support vector regression technique. Implementing only five peptide descriptors into this linear quantitative structure-activity relationship model resulted in an extremely robust and highly predictive model with calibration, leave-one-out and leave-20-out validation R(2)  of 0.9194, 0.9103, and 0.9214, respectively. We performed docking of the most potent calcitonin gene-related peptide antagonists with the calcitonin gene-related peptide receptor and demonstrated that peptide antagonists act by blocking access to the peptide-binding cleft. We also demonstrated the direct contact of residues 28-37 of the calcitonin gene-related peptide antagonists with the receptor. These results are in agreement with the conclusions drawn from the quantitative structure-activity relationship model, indicating that both electrostatic and steric factors should be taken into account when designing novel calcitonin gene-related peptide antagonists.
authors.affiliation: Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, P.O. Box 13145-1384, Tehran, Iran. anahita_kyani@yahoo.com
authors.forename: Anahita
authors.initials: A
authors.lastname: Kyani
authors.forename: Mohadeseh
authors.initials: M
authors.lastname: Mehrabian
authors.forename: Håvard
authors.initials: H
authors.lastname: Jenssen
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D008969:Molecular Sequence Data; D025341:Principal Component Analysis; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D058262:Receptor Activity-Modifying Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000737:chemistry / Q000378:metabolism; D012984:Software; D055672:Static Electricity
chemical_list: D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; C545502:RAMP1 protein, human; D058262:Receptor Activity-Modifying Protein 1; D018015:Receptors, Calcitonin Gene-Related Peptide