K. Satyamoorthy, Ph.D.
Director, Life Sciences Centre, Manipal University, India
Epigenetic Changes due to DNA Methylation in Human Epithelial Tumors
Extensive global hypomethylation in the genome and hypermthylation of selective tumor specific suppressor genes appears to be a hallmark of human cancers. Data suggests that hypermethylation of promoter region in genes is more closely related to subsequent gene expression; contrary to gene-body DNA methylation. The intricate balance between these two may contribute to the progressive process of development, differentiation and carcinogenesis. Epigenetic changes encompass, apart from DNA methylation, chromatin modifications through post-translational changes in histones and control by miRNAs. At the genome level, effects from these are compounded by copy number variations (CNVs) which may ultimately influence protein functions. From clinical perspective, changes in DNA methylation occur very early which are reversible and are influenced by environmental factors. Therefore, these can be potential resource for identifying therapeutic targets as well as biomarkers for early screening of cancer. Our current efforts in profiling genome wide DNA methylation changes in oral, cervical and breast cancers through DNA methylation microarray analysis has revealed number of alterations critical for survival, progression and metastatic behavior of tumors. Bioinformatics and functional analysis revealed several key regulatory molecules controlled by DNA methylation and suggests that DNA methylation changes in several CpG islands appear to co-segregate in the regions of miRNAs as well as in the CNVs. We have validated the signatures for methylation of CpG islands through bisufite sequencing for essential genes in clinical samples and have undertaken transcriptional and functional analysis in tumor cell lines. These results will be presented.
Jaap Heringa, Ph.D.
Director & Professor of Bioinformatics, IBIVU VU University Amsterdam, The Netherlands
Modeling strategy based on Petri-nets
In my talk I will introduce a formal modeling strategy based on Petri-nets, which are a convenient means of modeling biological processes. I will illustrate the capabilities of Petri-nets as reasoning vehicles using two examples: Haematopoietic stem cell differentiation in mice, and vulval development in C. elegance. The first system was modeled using a Boolean implementation, and the second using a coarse-grained multi-cellular Petri-net model. Concepts such as the model state space, attractor states, and reasoning to adapt the model to the biological reality will be discussed.
Nitish Sathyanrayanan, Sandesh Ganji and Holenarsipur Gundurao Nagendra.
Insilico Analysis of hypothetical proteins from Leishmania donovani: A Case study of a membrane protein of the MFS class reveals their plausible roles in drug resistance
Kala-azar or visceral leishmaniais (VL), caused by protozoan parasite Leishmania donovani, is one of the leading causes of morbidity and mortality in Bihar, India (Guerin et al. 2002; Mubayi et al. 2010). The disease is transmitted to the humans mainly by the vector, Phlebotmus argentipes, commonly known as Sand fly. The majority of VL (> 90%) occurs in only six countries: Bangladesh, India, Nepal, Sudan, Ethiopia and Brazil (Chappuis et al. 2007). In the Indian subcontinent, about 200 million people are estimated to be at risk of developing VL and this region harbors an estimated 67% of the global VL disease burden. The Bihar state only has captured almost 50% cases out of total cases in Indian sub-continent (Bhunia et al. 2013). ‘Conserved hypothetical’ proteins pose a challenge not just to functional genomics, but also to biology in general (Galperin and Koonin 2004). Leishmania donovani (strain BPK282A1) genome consists of a staggering ∼65% of hypothetical proteins. These uncharacterized proteins may enable better appreciation of signalling pathways, general metabolism, stress response and even drug resistance.
Rajasekhar Chekkara, Venkata Reddy Gorla and Sobha Rani Tenkayala
Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors
Polo-like kinase 1 (PLK1) is a significant enzyme with diverse biological actions in cell cycle progression, specifically mitosis. Suppression of PLK1 activity by small molecule inhibitors has been shown to inhibit cancer, being BI 2536 one of the most potent active inhibitor of PLK1 mechanism. Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies were carried out for a set of 54 compounds belonging to Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK1 inhibitors. A six-point pharmacophoremodel AAADDR, with three hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R) was developed by Phase module of Schrdinger suite Maestro 9. The generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the training set (r2 = 0.88, SD = 0.21, F = 57.7, N = 44) and for test set (Q2 = 0.51, RMSE = 0.41, PearsonR = 0.79, N = 10). The original set of compounds were docked into the binding site of PLK1 using Glide and the active residues of the binding site were analyzed. The most active compound H18 interacted with active residues Leu 59, Cys133 (glide score = −10.07) and in comparison of BI 2536, which interacted with active residues Leu 59, Cys133 (glide score = −10.02). The 3D-QSAR model suggests that hydrophobic and electron-withdrawing groups are essential for PLK1 inhibitory activity. The docking results describes the hydrogen bond interactions with active residues of these compounds. These results which may support in the design and development of novel PLK1 inhibitors.