title: Discovery of Novel α4β2 Neuronal Nicotinic Receptor Modulators through Structure-Based Virtual Screening.
abstract: We performed a hierarchical structure-based virtual screening utilizing a comparative model of the human α4β2 neuronal nicotinic acetylcholine receptor (nAChR) extracellular domain. Compounds were selected for experimental testing based on structural diversity, binding pocket location, and standard error of the free energy scoring function used in the screening. Four of the eleven in silico hit compounds showed promising activity with low micromolar IC50 values in a calcium accumulation assay. Two of the antagonists were also proven to be selective for human α4β2 vs human α3β4 nAChRs. This is the first report of successful discovery of novel nAChR antagonists through the use of structure-based virtual screening with a human nAChR homology model. These compounds may serve as potential novel scaffolds for further development of selective nAChR antagonists.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Mahasenan
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Pavlovicz
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Henderson
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Tatiana F
authors.initials: TF
authors.lastname: González-Cestari
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Bitna
authors.initials: B
authors.lastname: Yi
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Dennis B
authors.initials: DB
authors.lastname: McKay
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Biophysics Program, and Division of Pharmacology, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
keywords: AChBP; allosteric; nAChR; nicotinic acetylcholine receptor; noncompetitive antagonists; virtual screening