The 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway for isoprenoid biosynthesis has come under increased scrutiny as a target for novel antimalarial, antibacterial and herbicidal agents. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is a key enzyme of the pathway that catalyzes the rearrangement and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of 1-deoxy-D-xylulose 5-phosphate (DXP) to MEP. The unique properties of DXR make it a remarkable and rational target for drug design. First, it is a vital enzyme for synthesis of isoprenoids in algae, plants, several eubacteria including the pathogenic bacteria like Bacillus anthracis, Helicobacter pylori, Yersinia pestis, Mycobacterium tuberculosis and the malarial parasite, Plasmodium falciparum. Second, there are no functional equivalents to DXR in humans, making it an attractive target for therapeutic intervention. Third, DXR appears to be a valid target and the results from fosmidomycin (1), the only available DXR inhibitor under clinical trials, suggests synergistic effects with the lincosamide antibiotics, lincomycin and clindamycin. Despite drug design efforts in this area, no successful drug specifically designed to inhibit DXR has emerged yet. This review summarizes the recent and promising developments with respect to the current knowledge of the MEP pathway with emphasis on the understanding of the structure and the catalytic mechanism of the DXR enzyme and the global quest for therapeutically useful inhibitors of DXR.
Receptor tyrosine kinases (RTK) are transmembrane receptors that regulate signal transduction in cells. As a member of the TAM (Tyro-3, Axl, Mer) RTK subfamily, Axl regulates key processes such as cell growth, migration, aggregation, and apoptosis through several pathways. Its overexpression/overactivation has been underlined in several conditions, especially cancers, and in both chemotherapy and targeted therapy sensitivity loss. In this review, we propose to highlight the therapeutic implication of Axl, starting with the pathways it regulates, validating its interest as a therapeutic target, and defining the tools available to develop strategies for its inhibition. We especially focus on small molecule inhibitors, their structure, inhibition profile, and development stages. Mol Cancer Ther; 13(9); 2141-8. Ó2014 AACR.
The c-Jun N-terminal kinase (JNK) family, with its three members JNK1, JNK2, and JNK3, is a subfamily of mitogen-activated protein kinases. Involved in many aspects of cellular processes, JNK has been also associated with pathological states such as neurodegenerative diseases, inflammation, and cancers. In oncology, each isoform plays a distinct role depending on the context of the targeted tissue/organ, the tumor stage, and, most likely, the signaling pathway activated upstream. Consequently, the current challenge in finding new successful anti-JNK therapies is to design isoform-selective inhibitors of the JNKs. In this review, a particular focus is given to the JNK inhibitors that have been developed thus far when examining 3D structures of various JNK-inhibitor complexes. Using current data regarding structure-activity relationships and medicinal chemistry approaches, our objective is to provide a better understanding of the design and development of selective JNK inhibitors in the present and future.
Combined ligand-based and target-based drug design approaches provide a synergistic advantage over either method individually. Therefore, we set out to develop a powerful virtual screening model to identify novel molecular scaffolds as potential leads for the human KOP (hKOP) receptor employing a combined approach. Utilizing a set of recently reported derivatives of salvinorin A, a structurally unique KOP receptor agonist, a pharmacophore model was developed that consisted of two hydrogen bond acceptor and three hydrophobic features. The model was cross-validated by randomizing the data using the CatScramble technique. Further validation was carried out using a test set that performed well in classifying active and inactive molecules correctly. Simultaneously, a bovine rhodopsin based "agonist-bound" hKOP receptor model was also generated. The model provided more accurate information about the putative binding site of salvinorin A based ligands. Several protein structure-checking programs were used to validate the model. In addition, this model was in agreement with the mutation experiments carried out on KOP receptor. The predictive ability of the model was evaluated by docking a set of known KOP receptor agonists into the active site of this model. The docked scores correlated reasonably well with experimental pK (i) values. It is hypothesized that the integration of these two independently generated models would enable a swift and reliable identification of new lead compounds that could reduce time and cost of hit finding within the drug discovery and development process, particularly in the case of GPCRs.
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