Journal of Computer Science & Systems Biology

Background: High-throughput Omics technologies aimed at characterizing the molecular profile of diseases together with massive scientific literature on drugs and clinical trials opened the way for matching molecular profiles and drug mode of action in the realm of drug repositioning. We developed a computational analysis workflow for linking molecular targets, drugs, and diseases, and exemplified this approach for the immunosuppressive drug mycophenolate mofetil (MMF). Methods and Results: We first established a molecular MMF footprint consisting of deregulated Omics features from two transcriptomics datasets as well as from molecular features associated with MMF based on literature search methods. This footprint, consisting of 170 unique features, was used to identify diseases of relevance to MMF in the scientific literature using Medical Subject Heading (MeSH) terms. A disease enrichment score was calculated for each disease in the MeSH hierarchy, with highly ranked diseases being potentially associated to MMF. Diseases currently mentioned in clinical trials on MMF were used to validate our approach. The area under the curve was 0.78 when using the disease enrichment scores in order to discriminate between diseases currently in clinical trials and diseases not addressed by MMF with sensitivity and specificity values of 0.38 and 0.96 respectively. Among those diseases in clinical trials showing high scores were kidney diseases, multiple sclerosis, and systemic lupus erythematosus. Conclusion: We identified a significant recovery of drug-associated diseases for the example case of MMF solely utilizing a molecular profile of the drug mode of action. The approach furthermore provided hypotheses on further diseases approachable by the given drug.

A trinucleotide circular code is a set of trinucleotides allowing the reading frame in genes to be retrieved locally, i.e. anywhere in genes and in particular without start codon, and automatically with a window of a few nucleotides. In 1996, a common circular code X has been identified simultaneously in two large populations of eukaryotic and prokaryotic genes. The method proposed here identifies periodic signals of this code X in the two frameshift types (+1 and -1) of both eukaryotic and prokaryotic frameshift genes. As expected by the code theory, the circular code modulo 3 signals move in the same direction of translational frameshifting. Finally, in 68% of frameshift genes in the RECODE 2 database, the frameshift type (+1 and -1) is automatically identified using only this circular code periodic signal. This circular code information constitutes a new structural property of frameshift genes. It may be used directly or in association with existing methods to identify frameshift genes in genomes and their encoded proteins.

Pathogenic bacteria use the needle shaped Type III secretion system to inject effector proteins into the host cell. The SopB effector protein of Salmonella mediates invasion by evading the host immune response. Being a phosphoinositide phosphatase, it synthesizes phospholipids at the host cell membrane, after targeting host cell ubiquitin. Ubiquitination of SopB are known to control the biological activity of SopB at the plasma membrane. The identified SopB effector protein of Vibrio vulnificus which is a human pathogen found in the marine environment was homologous to SopB of Salmonella and E.coli. Structural superposition with available structure of SopB of Salmonella yielded a DNA linking domain similar to Salmonella SopB. Ubiquitination sites for SopB homolog in V.vulnificus was predicted by bioinformatics tools which was further supported by molecular docking studies. The ubiquitin binding sites were proposed to be structurally similar to the conserved ubiquitin binding motif of human polymerase complexed with ubiquitin (2KTF). The ubiquitin binding sites having Leu residue at 226, Leu 235 and Leu 234 were conserved whereas the hydrophobic Phe was replaced by Tyr at 223 in the sopB homolog of V.vulnificus. The conserved Glu 228 of SopB protein was predicted to be involved in imparting a electronegative potential in the ligand binding site. The ubiquitin molecule docked with SopB of V.vulnificus had Leu8 for binding interaction and recognition which was found to be similar to the ubiquitin-human polymerase complex. Thus the host immune response was predicted to be targeted by SopB effector in V.vulnificus by altering the ubiquitin pathway.