Heat shock proteins (Hsps) are ubiquitous and conserved molecules whose main function is to facilitate protein folding (molecular chaperone function). Some Hsps such as Hsp70 are also involved in protein folding, protein trafficking... more
Heat shock proteins (Hsps) are ubiquitous and
conserved molecules whose main function is to facilitate
protein folding (molecular chaperone function). Some
Hsps such as Hsp70 are also involved in protein folding,
protein trafficking and ubiquitination of misfolded
protein to facilitate their degradation. Hsps occur in functional networks and
hence their coordinated expression is important in
proteostasis. Some Hsps are stress-induced while others
are expressed constitutively. Because of their role as
sentinels of protein folding, it is not surprising that some
Hsps are essential and for this reason, they constitute
potential drug target. However, their high conservation is a snag to their
prospects as drug targets. In spite of this, drugs
targeting some Hsps especially Hsp90 show great
potential and some of them have entered clinical trials
for cancer treatment. In addition,
there are prospects to target Hsps in treatment of
infectious diseases such as malaria
Target discovery using the molecular approach, as opposed to the more traditional systems approach requires the study of the cellular or biological process underlying a condition or disease. The approaches that are employed by the... more
Target discovery using the molecular approach, as opposed to the more traditional systems approach
requires the study of the cellular or biological process underlying a condition or disease. The approaches
that are employed by the “bench” scientist may be genetic, genomic or proteomic and each has its rightful place
in the drug-target discovery process. Affinity-based proteomic techniques currently used in drug-discovery draw upon
several disciplines, synthetic chemistry, cell-biology, biochemistry and mass spectrometry. An important component of
such techniques is the probe that is specifically designed to pick out a protein or set of proteins from amongst the varied
thousands in a cell lysate. A second component, that is just as important, is liquid-chromatography tandem massspectrometry
(LC-MS/MS). LC-MS/MS and the supporting theoretical framework has come of age and is the tool of
choice for protein identification and quantification. These proteomic tools are critical to maintaining the drug-candidate
supply, in the larger context of drug discovery.
Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential... more
Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential therapeutic targets is critical for the development of effective treatment strategies. We used a systems biology approach to identify potential key regulatory factors in smoking-induced lung cancer. We first identified genes that were differentially expressed between smokers with normal lungs and those with cancerous lungs, then integrated these differentially expressed genes (DEGs) with data from a protein-protein interaction database to build a network model with functional modules for pathway analysis. We also carried out a gene set enrichment analysis of DEG lists using the Kinase Enrichment Analysis (KEA), Protein-Protein Interaction (PPI) hubs, and KEGG (Kyoto Encyclopedia of Genes and Genomes) databases. Twelve transcription factors were iden...
Background Infections caused by Salmonella enterica, a Gram-negative facultative anaerobic bacteria belonging to the family of Enterobacteriaceae, are major threats to the health of humans and animals. The recent availability of complete... more
Background Infections caused by Salmonella enterica, a Gram-negative facultative anaerobic bacteria belonging to the family of Enterobacteriaceae, are major threats to the health of humans and animals. The recent availability of complete genome data of pathogenic strains of the S. enterica gives new avenues for the identification of drug targets and drug candidates. We have used the genomic and metabolic pathway data to identify pathways and proteins essential to the pathogen and absent from the host. Methods We took the whole proteome sequence data of 42 strains of S. enterica and Homo sapiens along with KEGG-annotated metabolic pathway data, clustered proteins sequences using CD-HIT, identified essential genes using DEG database and discarded S. enterica homologs of human proteins in unique metabolic pathways (UMPs) and characterized hypothetical proteins with SVM-prot and InterProScan. Through this core proteomic analysis we have identified enzymes essential to the pathogen. Results The identification of 73 enzymes common in 42 strains of S. enterica is the real strength of the current study.We proposed all 73 unexplored enzymes as potential drug targets against the infections caused by the S. enterica. The study is comprehensive around S. enterica and simultaneously considered every possible pathogenic strain of S. enterica. This comprehensiveness turned the current study significant since, to the best of our knowledge it is the first subtractive core proteomic analysis of the unique metabolic pathways applied to any pathogen for the identification of drug targets. We applied extensive computational methods to shortlist few potential drug targets considering the druggability criteria e.g. Non-homologous to the human host, essential to the pathogen and playing significant role in essential metabolic pathways of the pathogen (i.e. S. enterica). In the current study, the subtractive proteomics through a novel approach was applied i.e. by considering only proteins of the unique metabolic pathways of the pathogens and mining the proteomic data of all completely sequenced strains of the pathogen, thus improving the quality and application of the results. We believe that the sharing of the knowledge from this study would eventually lead to bring about novel and unique therapeutic regimens against the infections caused by the S. enterica.
Abstract: Problem statement: The function of a protein is dependent on its three-dimensional structure. However, numerous proteins lacking intrinsic globular 3D structure under physiological conditions had been recognized. These proteins... more
Abstract: Problem statement: The function of a protein is dependent on its three-dimensional structure. However, numerous proteins lacking intrinsic globular 3D structure under physiological conditions had been recognized. These proteins are frequently involved in some of the most critical cellular control mechanisms and it appears that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions. Approach: A significant number of proteins known to be involved in protein deposition disorders were now considered to Be Intrinsically Unstructured Proteins (IUPs). For example, Aβ peptide and tau protein in Alzheimer’s disease, PrP in Prion’s disease and α-Synuclein in Parkinson’s disease. The disorder of intrinsically unstructured proteins (IUP's) was crucial to their functions. They may adopt defined but extended structures when bound to cognate l...
Target discovery using the molecular approach, as opposed to the more traditional systems approach requires the study of the cellular or biological process underlying a condition or disease. The approaches that are employed by the “bench”... more
Target discovery using the molecular approach, as opposed to the more traditional systems approach requires the study of the cellular or biological process underlying a condition or disease. The approaches that are employed by the “bench” scientist may be genetic, genomic or proteomic and each has its rightful place in the drug-target discovery process. Affinity-based proteomic techniques currently used in drug-discovery draw upon several disciplines, synthetic chemistry, cell-biology, biochemistry and mass spectrometry. An important component of such techniques is the probe that is specifically designed to pick out a protein or set of proteins from amongst the varied thousands in a cell lysate. A second component, that is just as important, is liquid-chromatography tandem massspectrometry (LC-MS/MS). LC-MS/MS and the supporting theoretical framework has come of age and is the tool of choice for protein identification and quantification. These proteomic tools are critical to maintai...
The function of a protein is dependent on its three-dimensional structure. However, numerous proteins lacking intrinsic globular 3D structure under physiological conditions had been recognized. These proteins are frequently involved in... more
The function of a protein is dependent on its three-dimensional structure. However, numerous proteins lacking intrinsic globular 3D structure under physiological conditions had been recognized. These proteins are frequently involved in some of the most critical cellular control mechanisms and it appears that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions. Approach: A significant number of proteins known to be involved in protein deposition disorders were now considered to Be Intrinsically Unstructured Proteins (IUPs). For example, Aβ peptide and tau protein in Alzheimer’s disease, PrP in Prion’s disease and α- Synuclein in Parkinson’s disease. The disorder of intrinsically unstructured proteins (IUP's) was crucial to their functions. They may adopt defined but extended structures when bound to cognate ligands. Their amino acid compositions were less hydrophobic than those of soluble proteins. They lack hydrophobic cores and hence did not become insoluble when heated. About 40% of eukaryotic proteins had at least one long (>50 residues) disordered region. Roughly 10% of proteins in various genomes had been predicted to be fully disordered. Presently over 100 IUP's had been identified; none are enzymes. Obviously, IUP's were greatly underrepresented in the Protein Data Bank, although there were few cases of an IUP bound to a folded (intrinsically structured) protein. Results: The five functional categories for intrinsically unstructured proteins and domains were entropic chains (bristles to ensure spacing, springs, flexible spacers/linkers), effectors (inhibitors and disassemblers), scavengers, assemblers and display sites. These IUPs could serve as potential targets for Structure Based Drug Design (SBDD) which stress on the transition from disordered to ordered confirmation through drug stimulation. Recently an unstructured domain of a regulatory protein had been found to be involved in inhibiting catalytic activity of insulin receptor and targeting this IUP would provide a new approach which can be employed in modifying insulin signaling in treatment of diabetes. IUPs were also involved diseases and disorders such as cardio vascular diseases, cancers and autoimmune disorders. Unstructured proteins had also been shown to be important components of invasion, survival and disguising strategies of pathogens such as Plasmodium falciparum. Conclusion: New greater focuses on proteins that were in some way unstructured normally would promise to provide a greater understanding of protein function particularly with respect to protein-protein interactions and hence can give new potential targets for future strategies.
