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Sultānpur Lodhi, India

Singh S.,JSBB | Singh A.K.,Indian Institute of Technology Bombay | Wadhwa G.,Apex Bioinformatics Center | Singh D.B.,Chhatrapati Shahu Ji Maharaj University | And 3 more authors.
Interdisciplinary Sciences: Computational Life Sciences | Year: 2016

Determination of the native geometry of the enzymes and ligand complexes is a key step in the process of structure-based drug designing. Enzymes and ligands show flexibility in structural behavior as they come in contact with each other. When ligand binds with active site of the enzyme, in the presence of cofactor some structural changes are expected to occur in the active site. Motivation behind this study is to determine the nature of conformational changes as well as regions where such changes are more pronounced. To measure the structural changes due to cofactor and ligand complex, enzyme in apo, holo and ligand-bound forms is selected. Enzyme data set was retrieved from protein data bank. Fifteen triplet groups were selected for the analysis of structural changes based on selection criteria. Structural features for selected enzymes were compared at the global as well as local region. Accessible surface area for the enzymes in entire triplet set was calculated, which describes the change in accessible surface area upon binding of cofactor and ligand with the enzyme. It was observed that some structural changes take place during binding of ligand in the presence of cofactor. This study will helps in understanding the level of flexibility in protein–ligand interaction for computer-aided drug designing. © 2015, International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg. Source


Lodhi S.S.,Jiwaji University | Lodhi S.S.,Apex Bioinformatics Center | Farmer R.,Sam Higginbottom Institute of Agriculture, Technology and Sciences | Singh A.K.,Indian Institute of Technology Bombay | And 2 more authors.
Molecular Biology Reports | Year: 2014

Rab3A is expressed predominantly in brain and synaptic vesicles. Rab3A is involved specifically in tethering and docking of synaptic vesicles prior to fusion which is a critical step in regulated release of neurotransmitters. The precise function of Rab3A is still not known. However, up-regulation of Rab3A has been reported in malignant neuroendocrine and breast cancer cells. In the present study, the structure of Rab3A protein was generated using MODELLER 9v8 software. The modeled protein structure was validated and subjected to molecular docking analyses. Docking with GTP was carried out on the binding site of Rab3A using GOLD software. The Rab3A-GTP complex has best GOLD fitness value of 77.73. Ligplot shows hydrogen bondings (S16, S17, V18, G19, K20, T21, S22, S31, T33, A35, S38, T39 and G65) and hydrophobic interacting residues (F25, F32, P34, F36, V37, D62 and A64) with the GTP ligands in the binding site of Rab3A protein. Here, the ligand molecules of NCI diversity set II from the ZINC database against the active site of the Rab3A protein were screened. For this purpose, the incremental construction algorithm of GLIDE and the genetic algorithm of GOLD were used. Docking results were analyzed for top ranking compounds using a consensus scoring function of X-Score to calculate the binding affinity and Ligplot was used to measure protein-ligand interactions. Five compounds which possess good inhibitory activity and may act as potential high affinity inhibitors against Rab3A active site were identified. The top ranking molecule (ZINC13152284) has a Glide score of -6.65 kcal/mol, X-Score of -3.02 kcal/mol and GOLD score of 64.54 with 03 hydrogen bonds and 09 hydrophobic contacts. This compound is thus a good starting point for further development of strong inhibitors. © 2014 Springer Science+Business Media. Source


Lodhi S.S.,Jiwaji University | Lodhi S.S.,Apex Bioinformatics Center | Farmer R.,Sam Higginbottom Institute of Agriculture, Technology and Sciences | Jaiswal Y.K.,Jiwaji University | Wadhwa G.,Apex Bioinformatics Center
Interdisciplinary Sciences: Computational Life Sciences | Year: 2015

Among CYPs, CYP2A sub-family is well known for its function to metabolise xenobiotics. CYP2A includes three members: CYP2A6, CYP2A7 and CYP2A13. Of these three proteins, structure and function of CYP2A6 and CYP2A13 are widely studied, whereas very little study has been carried out on CYP2A7. In the initial in vitro studies on CYP2A7, full protein in its active form could not be expressed. The exact structure and function of CYP2A7 is still not revealed. However, up-regulation of CYP2A7 has been reported in malignant oesophageal cells and colon cancer cells. In the present study, we generated the structure of CYP2A7 protein. The modelled proteins were validated and subjected to molecular docking analyses. The energy and RMSD calculations demonstrated that the protein is highly conserved in nature, i.e., the protein is not much flexible. Here the ligand molecules of NCI Diversity Set II from the ZINC database against the active site of the CYP2A7 protein were screened. Five compounds that possess good inhibitory activity against CYP2A7 active site were identified. The top ranking molecule (ZINC01572309) has a minimum energy score of −12.0 kcal/Mol. This compound is thus a good starting point for further development of strong inhibitors. Our in silico approach could help in better structural and functional analysis of CYP2A7. Apart from structural description of CYP2A7, elaboration of binding sites for inhibitors provides us with an opportunity to utilise binding pockets in targeted inactivation of this protein for further research. © 2015, International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg. Source


Gautam B.,Sam Higginbottom Institute of Agriculture, Technology and Sciences | Singh G.,Sam Higginbottom Institute of Agriculture, Technology and Sciences | Singh A.K.,Apex Bioinformatics Center | Wadhwa G.,Apex Bioinformatics Center
Indian Journal of Biotechnology | Year: 2013

Toxoplasma gondii is an obligate, intracellular, apicomplexan parasite that can infect a wide range of warm-blooded animals including humans. In humans and other intermediate hosts, Toxoplasma develops into chronic infection that cannot be eliminated by host's immune response or by currently used drugs. The ability of the parasite to convert to the bradyzoite stage and to live inside slow-growing cysts that can go unnoticed by the host immune system allows for the persistence of parasite throughout the life of the infected host. Little is known, however, about how bradyzoites manipulate their host cell. Large scale microarray experiments are becoming increasingly routine, particularly those which track a number of different cell lines through time. This time course information providesvaluable insight into dynamics of various biological processes. The proper statistical analysis, however, requires the use of more sophisticated tools and complex statistical models. In the current study, the open-source R programming environment in conjunction with the open-source Bioconductor software was used to analyze microarray data of T. gondii. Several statistical analysis procedures like (log) fold changes in conjunction with ordinary and moderated t-statistics were used to determine differentially expressed genes. The differentially expressed genes were subjected to cluster analysis, followed by the annotation of the up and down regulated genes based on the gene ontology. The findings in the present study suggest the overall effect of the gene expression changes is to modulate thekey metabolic pathways leading to compromised host immune response, enhancement in programmed cell death, depression in cell proliferation process and induction of various diseases. Source

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