Source Of Drug Targets Research Articles

Systems Chemical Genetics-Based Drug Discovery: Prioritizing Agents Targeting Multiple/Reliable Disease-Associated Genes as Drug Candidates.

Genetic disease genes are considered a promising source of drug targets. Most diseases are caused by more than one pathogenic factor; thus, it is reasonable to consider that chemical agents targeting multiple disease genes are more likely to have desired activities. This is supported by a comprehensive analysis on the relationships between agent activity/druggability and target genetic characteristics. The therapeutic potential of agents increases steadily with increasing number of targeted disease genes, and can be further enhanced by strengthened genetic links between targets and diseases. By using the multi-label classification models for genetics-based drug activity prediction, we provide universal tools for prioritizing drug candidates. All of the documented data and the machine-learning prediction service are available at SCG-Drug (http://zhanglab.hzau.edu.cn/scgdrug).

Constitutively active BRS3 is a genuinely orphan GPCR in placental mammals.

G protein–coupled receptors (GPCRs) play an important role in physiology and disease and represent the most productive drug targets. Orphan GPCRs, with their endogenous ligands unknown, were considered a source of drug targets and consequently attract great interest to identify their endogenous cognate ligands for deorphanization. However, a contrary view to the ubiquitous existence of endogenous ligands for every GPCR is that there might be a significant overlooked fraction of orphan GPCRs that function constitutively in a ligand-independent manner only. Here, we investigated the evolution of the bombesin receptor–ligand family in vertebrates in which one member—bombesin receptor subtype-3 (BRS3)—is a potential orphan GPCR. With analysis of 17 vertebrate BRS3 structures and 10 vertebrate BRS3 functional data, our results demonstrated that nonplacental vertebrate BRS3 still connects to the original ligands—neuromedin B (NMB) and gastrin-releasing peptide (GRP)—because of adaptive evolution, with significantly changed protein structure, especially in three altered key residues (Q127R, P205S, and R294H) originally involved in ligand binding/activation, whereas the placental mammalian BRS3 lost the binding affinity to NMB/GRP and constitutively activates Gs/Gq/G12 signaling in a ligand-independent manner. Moreover, the N terminus of placental mammalian BRS3 underwent positive selection, exhibiting significant structural differences compared to nonplacental vertebrate BRS3, and this domain plays an important role in constitutive activity of placental mammalian BRS3. In conclusion, constitutively active BRS3 is a genuinely orphan GPCR in placental mammals, including human. To our knowledge, this study identified the first example that might represent a new group of genuinely orphan GPCRs that will never be deorphanized by the discovery of a natural ligand and provided new perspectives in addition to the current ligand-driven GPCR deorphanization.

Comprehensive Mass Spectrometric Survey of Streptococcus pyogenes Subcellular Proteomes.

Streptococcus pyogenes is a major global health burden causing a wide variety of diseases. Because a vaccine against this bacterium is still lacking, vaccine candidates or antimicrobial therapies are urgently needed. Here we use an invasive and clinically relevant streptococcal M1 serotype to characterize the bacterial proteome in-depth. An elaborate fractionation technique is employed to separate the different cell fractions, followed by shotgun mass-spectrometry analysis, allowing us to confirm the expression of nearly two-thirds (1022) of the 1690 open reading frames predicted for the streptococcal M1 reference proteome. In contrast with other studies, we present the entire isolated membrane proteome, which opens up a whole new source for drug targets. We show both the unique and most prevalent proteins for each cellular fraction and analyze the presence of predicted cell-wall-anchored proteins and lipoproteins. With our approach, we also identify a variety of novel proteins whose presence has not been reported in previous proteome studies. Proteins of interest, potential virulence factors, and drug or vaccine targets are discussed for each cellular fraction. Overall, the results of this work represent the so-far widest proteomic approach to characterize the protein composition and localization in S. pyogenes.

Editorial (The Ubiquitin Proteasome System as a Source of Drug Targets for Cancer Therapy)

Editorial (The Ubiquitin Proteasome System as a Source of Drug Targets for Cancer Therapy)

Vitamin B metabolism in Plasmodium falciparum as a source of drug targets

The malaria parasite Plasmodium falciparum depends primarily on nutrient sources from its human host. Most compounds, such as glucose, purines, amino acids, as well as cofactors and vitamins, are abundantly available in the host cell, and can be readily salvaged by the parasite. However, in some cases the parasite can also synthesize cofactors de novo in reactions that appear to be essential. Importantly, the three biosynthetic pathways that produce vitamins B(1), B(6) and B(9) are absent from the host, but are well established in P. falciparum. This review summarizes and updates the current knowledge of vitamin B de novo synthesis and salvage in P. falciparum and focuses on their potential as targets for drug intervention.