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.

Scanning structure-activity relationships with structure-activity similarity and related maps: from consensus activity cliffs to selectivity switches.

Abstract: Systematic description of structure–activity relationships (SARs) of data sets and structure–property relationships (SPRs) is of paramount importance in medicinal chemistry and other research fields. To this end, structure–activity similarity (SAS) maps are one of the first tools proposed to describe SARs using the concept of activity landscape modeling. One of the major goals of the SAS maps is to identify activity cliffs defined as chemical compounds with high similar structure but unexpectedly very different biological activity. Since the first publication of the SAS maps more than ten years ago, these tools have evolved and adapted over the years to analyze various types of compound collections, including structural diverse and combinatorial sets with activity for one or multiple biological end points. The development of SAS maps has led to general concepts that are applicable to other activity landscape methods such as “consensus activity cliffs” (activity cliffs common to a series of representations...

Empagliflozin for Type 2 Diabetes Mellitus: An Overview of Phase 3 Clinical Trials.

Abstract: Introduction: Sodium glucose cotransporter 2 (SGLT2) inhibitors have a unique mecha-nism of action leading to excretion of glucose in the urine and subsequent lowering of plasma glu-cose. This mechanism is independent of β-cell function; thus, these agents are effective treatment for type 2 diabetes mellitus (T2DM) at theoretically any disease stage. This class should not confer an additional risk of hypoglycemia (unless combined with insulin or an insulin secretagogue) and has the potential to be combined with other classes of glucose-lowering agents. Empagliflozin is one of three currently approved SGLT2 inhibitors in the United States, and has shown a favorable benefit-risk ratio in phase 3 clinical trials as monotherapy and as add-on to other glucose-lowering therapy in broad patient populations. In addition to its glucose-lowering effects, empagliflozin has been shown to reduce body weight and blood pressure without a compensatory increase in heart rate. Moreover, on top of standard of care, empagliflozin is the first glucose-lowering agent to demonstrate cardiovas-cular risk reduction in patients at high risk of cardiovascular disease in a prospective outcomes trial: a 14% reduction in risk of the 3-point composite endpoint of death from cardiovascular causes, nonfa-tal myocardial infarction, or nonfatal stroke. Like other SGLT2 inhibitors, empagliflozin is associated with a higher rate of genital mycotic infections than placebo and has the potential for volume deple-tion–associated events.

Unique Ligand Binding Sites on CXCR4 Probed by a Chemical Biology Approach: Implications for the Design of Selective Human Immunodeficiency Virus Type 1 Inhibitors

Abstract: The chemokine receptor CXCR4 plays an important role as the receptor for the normal physiological function of stromal cell-derived factor 1alpha (SDF-1alpha) and the coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) into the cell. In a recent work (S. Tian et al., J. Virol. 79:12667-12673, 2005), we found that many residues throughout CXCR4 transmembrane (TM) and extracellular loop 2 domains are specifically involved in interaction with HIV-1 gp120, as most of these sites did not play a role in either SDF-1alpha binding or signaling. These results provided direct experimental evidence for the distinct functional sites on CXCR4 for HIV-1 and the normal ligand SDF-1alpha. To further understand the CXCR4-ligand interaction and to develop new CXCR4 inhibitors to block HIV-1 entry, we have recently generated a new family of unnatural chemokines, termed synthetically and modularly modified (SMM) chemokines, derived from the native sequence of SDF-1alpha or viral macrophage inflammatory protein II (vMIP-II). These SMM chemokines contain various de novo-designed sequence replacements and substitutions by d-amino acids and display more enhanced CXCR4 selectivity, binding affinities, and/or anti-HIV activities than natural chemokines. Using these novel CXCR4-targeting SMM chemokines as receptor probes, we conducted ligand binding site mapping experiments on a panel of site-directed mutants of CXCR4. Here, we provide the first experimental evidence demonstrating that SMM chemokines interact with many residues on CXCR4 TM and extracellular domains that are important for HIV-1 entry, but not SDF-1alpha binding or signaling. The preferential overlapping in the CXCR4 binding residues of SMM chemokines with HIV-1 over SDF-1alpha illustrates a mechanism for the potent HIV-1 inhibition by these SMM chemokines. The discovery of distinct functional sites or conformational states influenced by these receptor sites mediating different functions of the natural ligand versus the viral or synthetic ligands has important implications for drug discovery, since the sites shared by SMM chemokines and HIV-1 but not by SDF-1alpha can be targeted for the development of selective HIV-1 inhibitors devoid of interference with normal SDF-1alpha function.