Molecular Basis of Action of a Small-Molecule Positive Allosteric Modulator Agonist at the Type 1 Cholecystokinin Holoreceptor.

Allosteric modulation of receptors provides mechanistic safety while effectively achieving biologic endpoints otherwise difficult or impossible to obtain by other means. The theoretical case has been made for the development of a positive allosteric modulator (PAM) of the type 1 cholecystokinin receptor (CCK1R) having minimal intrinsic agonist activity to enhance meal-induced satiety for the treatment of obesity, while reducing the risk of side effects and/or toxicity. Unfortunately, such a drug does not currently exist.

Identification of previously unrecognized antiestrogenic chemicals using a novel virtual screening approach.

The physiological roles of estrogen in sexual differentiation and development, female and male reproductive processes, and bone health are complex and diverse. Numerous natural and synthetic chemical compounds, commonly known as endocrine disrupting chemicals (EDCs), have been shown to alter the physiological effects of estrogen in humans and wildlife. As such, these EDCs may cause unanticipated and even undesirable effects.

Enrichment of ligands for the serotonin receptor using the Shape Signatures approach.

Shape Signatures, a new 3-dimensional molecular comparison method, has been adapted to rank ligands of the serotonin receptors. A set of 825 agonists and 400 antagonists together with approximately 10,000 randomly chosen compounds from the NCI database were used in this study. Both 1D and 2D Shape Signature databases were created, and enrichment studies were carried out.