Torrey Pines Institute for Molecular Studies

About: Torrey Pines Institute for Molecular Studies is a nonprofit organization based out in San Diego, California, United States. It is known for research contribution in the topics: Antigen & T cell. The organization has 2323 authors who have published 2217 publications receiving 112618 citations.

Integrating virtual screening and combinatorial chemistry for accelerated drug discovery.

Abstract: Virtual screening is increasingly being used in drug discovery programs with a growing number of successful applications. Experimental methodologies developed to speed up the drug discovery processes include high throughput screening and combinatorial chemistry. The complementarities between computational and experimental screenings have been recognized and reviewed in the literature. Computational methods have also been used in the combinatorial chemistry field, in particular in library design. However, the integration of computational and combinatorial chemistry screenings has been attempted only recently. Combinatorial libraries (experimental or virtual) represent a notable source of chemically related compounds. Advances in combinatorial chemistry and deconvolution strategies, have enabled the rapid exploration of novel and dense regions in the chemical space. The present review is focused on the integration of virtual and experimental screening of combinatorial libraries. Applications of virtual screening to discover novel anticancer agents and our ongoing efforts towards the integration of virtual screening and combinatorial chemistry are also discussed.

Identification of substrate-analog trypsin inhibitors through the screening of synthetic peptide combinatorial libraries.

Abstract: Synthetic peptide combinatorial libraries (SPCLs), which are made up in total of tens to hundreds of millions of peptides, enable the systematic screening for biologically active peptides in virtually all in vitro and even in vivo assay systems. In the current study, the applicability of this method to the identification of peptide enzyme inhibitors was investigated using trypsin as the model enzyme. A specifically designed library of hexapeptide mixtures was synthesized on cotton carriers and screened. The synthetic approach, using cotton as a solid support, was modified so that the deprotected peptides remained attached to the cotton carrier until they were released into solution directly prior to being assayed. Following an iterative process of synthesis and screening, in which all of the positions of the sequence were successively defined, a number of individual hexapeptides with trypsin inhibitory activity were identified. The most active, defined individual peptide sequence was then reincorporated into a new library, now made up of dodecapeptide mixtures. The iterative screening and synthesis of this library led to a dodecapeptide with improved inhibitory activity when compared to the hexapeptide from which it was derived.

Stability, Dynamics, and Selectivity in the Assembly of Hydrogen-Bonded Hexameric Capsules

Abstract: Fluorescence resonance energy transfer (FRET) was employed to monitor the dynamics of hydrogen-bonded hexameric assemblies formed from resorcin[4]arenes and pyrogallol[4]arenes. Studies were designed to provide further insights into the degree of assembly and stability of these self-assembled capsules at the micro- to nanomolar concentration ranges that are not accessible by NMR studies. The results of this investigation reveal factors that influence the self-assembly of these macrocycles into hexameric capsules. Pyrogallolarenes are very sensitive to the concentration of mixing, with an increase in the equilibration half-life from 36 min at 250 nM to 156 min at 10 microM. The resorcinarenes showed little difference in exchange rates over the same concentration range. The temperature of mixing of the macrocycles was found to be important for both systems with a 12-fold increase in exchange rates over a 20 degree range for the pyrogallolarenes and a 2-fold rate increase for the resorcinarenes over the same temperature range. The stability of the capsules to polar additives such as methanol was probed, with the pyrogallolarenes requiring a higher percentage (1.6% v/v in dichloromethane) of methanol to disassemble the capsules than the resorcinarenes (1.0% v/v in dichloromethane). Pyrogallolarenes assemble in both anhydrous and wet solvents whereas water-saturated solvents are necessary to facilitate the formation of resorcinarene capsules. In addition to these studies, evidence of strict self-sorting in the formation of distinct pyrogallolarene and resorcinarene hexamers was obtained.

Challenges for opioid receptor nomenclature: IUPHAR Review 9

Abstract: Recent developments in the study of the structure and function of opioid receptors raise significant challenges for the definition of individual receptor types and the development of a nomenclature that precisely describes isoforms that may subserve different functions in vivo. Presentations at the 2013 meeting of the International Narcotics Research Conference in Cairns, Australia, considered some of the new discoveries that are now unravelling the complexities of opioid receptor signalling. Variable processing of opioid receptor messenger RNAs may lead to the presence of several isoforms of the μ receptor. Each opioid receptor type can function either as a monomer or as part of a homo- or heterodimer or higher multimer. Additionally, recent evidence points to the existence of agonist bias in the signal transduction pathways activated through μ receptors, and to the presence of regulatory allosteric sites on the receptors. This brief review summarizes the recent discoveries that raise challenges for receptor definition and the characterization of signal transduction pathways activated by specific receptor forms. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2