Fragment-based approach to identify IDO1 inhibitor building blocks.

Indoleamine 2,3-dioxygenase 1 (IDO1) is attracting a great deal of interest as drug target in immune-oncology being highly expressed in cancer cells and participating to the tumor immune-editing process. Although several classes of IDO1 inhibitors have been reported in literature and patent applications, only few compounds have proved optimal pharmacological profile in preclinical studies to be advanced in clinical trials. Accordingly, the quest for novel structural classes of IDO1 inhibitors is still open. In this paper, we report a fragment-based screening campaign that combines Water-LOGSY NMR experiments and microscale thermophoresis approach to identify fragments that may be helpful for the development of novel IDO1 inhibitors as therapeutic agents in immune-oncology disorders.

Binding properties of different categories of IDO1 inhibitors: a microscale thermophoresis study.

AIM: Inhibition of IDO1 is a strategy pursued in the immune-oncology pipeline for the development of novel anticancer therapies. At odds with an ever-increasing number of inhibitors being disclosed in the literature and patent applications, only very few compounds have hitherto advanced in clinical settings. MATERIALS & METHODS: We have used MicroScale Thermophoresis analysis and docking calculations to assess on a quantitative basis the binding properties of distinct categories of inhibitors to IDO1. RESULTS: Results shed further light on hidden molecular aspects governing the recognition by the enzyme of compounds with different mechanism of inhibition. CONCLUSION: Results pinpoint specific binding features of distinct inhibitors to IDO1 that offer clues for the design of next-generation inhibitors of the enzyme.

Docking Studies and Molecular Dynamic Simulations Reveal Different Features of IDO1 Structure.

In the last decade, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted a great deal of attention being recognized as key regulator of immunosuppressive pathways in the tumor immuno-editing process. Several classes of inhibitors have been developed as potential anticancer agents, but only few of them have advanced in clinical trials. Hence, the quest of novel potent and selective inhibitors of the enzyme is still active and mostly pursued by structure-based drug design strategies based on early and more recent crystal structures of IDO1. Combining docking studies and molecular dynamic simulations, in this work we have comparatively investigated the structural features of each crystal structure of IDO1. The results pinpoint different features in specific crystal structures of the enzyme that may benefit the medicinal chemistry arena aiding the design of novel potent and selective inhibitors of IDO1.

Beyond bile acids: targeting Farnesoid X Receptor (FXR) with natural and synthetic ligands.

The modulation of FXR receptor remains an attractive area in drug discovery to develop novel therapeutic opportunities for liver and metabolic disorders. Despite the large variety of FXR ligands reported so far, only a very restricted number of agonists have entered in clinical settings. In this review article we provide the reader with an overview on the different classes of natural and synthetic ligands that have been developed by academic groups and pharmaceutical companies to target FXR. We discuss their structure-activity relationships, analyzing the binding modes that some of these compounds adopt to interact with the receptor.

Fitting the complexity of GPCRs modulation into simple hypotheses of ligand design.

G-protein coupled receptors (GPCR(s)) are a large family of membrane-bound receptors that mediate a wide range of physiologic responses to hormones, neurotransmitters and dietary lipids, which represent an important class of drug targets. Significant chemical space regions have been explored both in the academia and by pharmaceutical companies, in the quest for new GPCR modulators as potential therapeutic agents. This accumulated body of evidence provides new opportunities to evaluate potential features of GPCR agonists and antagonists, and how to distinguish them. In this study, the chemical space covered within the WOMBAT database by GPCRs modulators was investigated with the aim of identifying specific molecular determinants that distinguish GPCR agonists from antagonists. While instrumental to get insights into the design strategies of GPCRs modulators, the results of this study provide novel clues on the molecular mechanisms that underlie the complexity of GPCR modulation.