The Discovery Core will utilize virtual and convenfional screening approaches to identify small molecules that modulate GPCR interactions with G proteins, GRKs and p-arrestins. In addition, a human lenfiviral shRNA library will be screened for effects on cAMP producfion, Ca^* flux, and steroid sensitivity in human airway smooth muscle cells. Small molecule and lenfiviral library screening will be conducted in the KCC Discovery Core at Thomas Jefferson University (www.kimmelcancercenter.orq/kcc/kccnew/research/resources/discoverv/). which provides liquid handling and optical detection for high-throughput screening of arrayed libraries of small molecules, as well as shRNA transducfion and target identification capabilities. Assays for arrayed library screening include cAMP-Glo and EPAC for cAMP quantification, Fura2/AM for Ca^* flux and BRET^ to quantify p-arrestin recruitment. The Discovery Core maintains several compound collections, including the US Drug Collection from Microsource Diversity and the Diverset and CNS libraries from Chembridge, and can array small molecule libraries that are acquired from public or private entifies, or that are suggested through virtual screening efforts. Since several GRKs have been characterized by X-ray crystallography, it is also possible to perform virtual screening using computational modeling and docking approaches. These models will be evaluated and refined with an all-atom physics-based potenfial function approach using CHARMM for energy minimization, refinement, conformational sampling and dynamics. CHARMM-based molecular docking and scoring approaches will be used to predict relevant GRK-small molecule interacfions.
These studies should identify small molecules that will be able to enhance relaxation or inhibit constriction of human airway smooth muscle. These molecules should serve as good leads for the development of more effective treatments of human airway diseases such as asthma.
|Aisenberg, William H; Huang, Jessie; Zhu, Wanqu et al. (2016) Defining an olfactory receptor function in airway smooth muscle cells. Sci Rep 6:38231|
|Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) Î²-arrestin-biased signaling through the Î²2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16|
|Carr 3rd, Richard; Koziol-White, Cynthia; Zhang, Jie et al. (2016) Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms. Mol Pharmacol 89:94-104|
|Ghosh, Arnab; Koziol-White, Cynthia J; Asosingh, Kewal et al. (2016) Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma. Proc Natl Acad Sci U S A 113:E2355-62|
|Xie, Yan; Jiang, Haihong; Zhang, Qian et al. (2016) Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis. Respir Res 17:103|
|Pera, Tonio; Penn, Raymond B (2016) Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones. Pharmacol Ther 164:82-96|
|Dileepan, Mythili; Sarver, Anne E; Rao, Savita P et al. (2016) MicroRNA Mediated Chemokine Responses in Human Airway Smooth Muscle Cells. PLoS One 11:e0150842|
|Kim, Donghwa; Pauer, Susan H; Yong, Hwan M et al. (2016) Î²2-Adrenergic Receptors Chaperone Trapped Bitter Taste Receptor 14 to the Cell Surface as a Heterodimer and Exert Unidirectional Desensitization of Taste Receptor Function. J Biol Chem 291:17616-28|
|An, Steven S; Mitzner, Wayne; Tang, Wan-Yee et al. (2016) An inflammation-independent contraction mechanophenotype of airway smooth muscle in asthma. J Allergy Clin Immunol 138:294-297.e4|
|Billington, Charlotte K; Penn, Raymond B; Hall, Ian P (2016) Î²2 Agonists. Handb Exp Pharmacol :|
Showing the most recent 10 out of 38 publications