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Docking into Homology Models in tandem with Structure Activity Relationships: Bradykinin B2 Receptor Complexed with Non‐opioid Dynorphin A Analogues
Author(s) -
Chan Christopher,
Lee Yeon Sun,
Hruby Victor
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.842.2
Subject(s) - pharmacophore , docking (animal) , homology modeling , g protein coupled receptor , chemistry , bradykinin , kallidin , receptor , in silico , computational biology , pharmacology , stereochemistry , biochemistry , biology , medicine , enzyme , kinin , nursing , gene
There have been multiple studies validating the use of homology modeling in tandem with ligand docking software in developing novel drugs for G protein‐coupled receptor (GPCR) systems. However, homology modeling is a viable, albeit less accurate, alternative to crystal structures in binding site determination via in silico systems. Bradykinin B2 receptor (B2R) is implicated, following nerve injury, in promoting neuropathic pain. Until recently, bradykinin and kallidin were thought to be the only endogenous ligands for B2R. Thus, B2R activation by dynorphin A (Dyn A) – despite being structurally dissimilar to bradykinin– during chronic pain has garnered recent interest in developing a drug to modulate hyperalgesia. Coupled with recent structure‐activity relationships (SAR) studies, ligand‐receptor docking computations are refined and restrained to produce a structural model for future drug design. Default settings were used for Glide SP and Glide SP‐Peptide ligand receptor docking near the second extracellular loop (ECL2). We correlate binding affinities of Dyn A analogues to their binding energies (performed by Glide), pose RMSD, and Generally Applicable Replacement rmsD (GARD) scores to determine a homology model of BDKR2. Future progress would involve refining the results found by incorporating known residue interactions with the minimum pharmacophore.