title: Insights into the structural determinants required for high-affinity binding of chiral cyclopropane-containing ligands to α4β2-nicotinic acetylcholine receptors: an integrated approach to behaviorally active nicotinic ligands.
abstract: Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human α4β2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.
authors.forename: Han-Kun
authors.initials: HK
authors.lastname: Zhang
authors.forename: J Brek
authors.initials: JB
authors.lastname: Eaton
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Yu
authors.forename: Mieke
authors.initials: M
authors.lastname: Nys
authors.forename: Angelica
authors.initials: A
authors.lastname: Mazzolari
authors.forename: René
authors.initials: R
authors.lastname: van Elk
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.forename: Vadim
authors.initials: V
authors.lastname: Alexandrov
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Emily
authors.initials: E
authors.lastname: Sabath
authors.forename: Allison
authors.initials: A
authors.lastname: Fedolak
authors.forename: Daniela
authors.initials: D
authors.lastname: Brunner
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Lukas
authors.forename: Giulio
authors.initials: G
authors.lastname: Vistoli
authors.forename: Chris
authors.initials: C
authors.lastname: Ulens
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003521:Cyclopropanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015195:Drug Design; D054333:Drug Partial Agonism; D004355:Drug Stability; D005461:Fluorine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D018722:Nicotinic Agonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011077:Polychaeta; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D003521:Cyclopropanes; D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D005461:Fluorine; C030797:cyclopropane