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Jayashree Biswal Prajisha Jayaprakash Rayala Suresh Kumar Ganesh Venkatraman Saritha Poopandi Raghu Rangasamy 《Journal of biomolecular structure & dynamics》2020,38(1):13-31
Abstractp21-activated kinases (Paks) play an integral component in various cellular diverse processes. The full activation of Pak is dependent upon several serine residues present in the N-terminal region, a threonine present at the activation loop, and finally the phosphorylation of these residues ensure the complete activation of Pak1. The present study deals with the identification of novel potent candidates of Pak1 using computational methods as anti-cancer compounds. A diverse energy based pharmacophore (e-pharmacophore) was developed using four co-crystal inhibitors of Pak1 having pharmacophore features of 5 (DRDRR), 6 (DRHADR), and 7 (RRARDRP and DRRDADH) hypotheses. These models were used for rigorous screening against e-molecule database. The obtained hits were filtered using ADME/T and molecular docking to identify the high affinity binders. These hits were subjected to hierarchical clustering using dendritic fingerprint inorder to identify structurally diverse molecules. The diverse hits were scored against generated water maps to obtain WM/MM ΔG binding energy. Furthermore, molecular dynamics simulation and density functional theory calculations were performed on the final hits to understand the stability of the complexes. Five structurally diverse novel Pak1 inhibitors (4835785, 32198676, 32407813, 76038049, and 32945545) were obtained from virtual screening, water thermodynamics and WM/MM ΔG binding energy. All hits revealed similar mode of binding pattern with the hinge region residues replacing the unstable water molecules in the binding site. The obtained novel hits could be used as a platform to design potent drugs that could be experimentally tested against cancer patients having increased Pak1 expression. 相似文献
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Naveen Admala Reddy Gopinath Adusumilli Raghu Devanna Rohra G Mayur Saravanan Pichai Sharmila Arujnan 《Indian journal of human genetics》2013,19(4):459-464
INTRODUCTION:
Non-syndromic tooth agenesis is a congenital anomaly with significant medical, psychological, and social ramifications. There is sufficient evidence to hypothesize that locus for this condition can be identified by candidate genes.AIM OF THE STUDY:
The aim of this study was to test whether MSX1 671 T > C gene variant was involved in etiology of non-syndromic tooth agenesis in Raichur patients.MATERIALS AND METHODS:
Blood samples were collected with informed consent from 50 subjects having non-syndromic tooth agenesis and 50 controls. Genomic deoxyribonucleic acid (DNA) was extracted from the blood samples, polymerase chain reaction (PCR) was performed, and restriction fragment length polymorphism (RFLP) was performed for digestion products that were evaluated.RESULTS:
The results showed positive correlation between MSX1671 T > C gene variant and non-syndromic tooth agenesis in Raichur patients.CONCLUSION:
MSX1 671 T > C gene variant may be a good screening marker for non-syndromic tooth agenesis in Raichur patients. 相似文献7.
Raghu Pullakhandam 《Archives of biochemistry and biophysics》2009,485(2):115-895
Biophysical evidences suggest that transthyretin (TTR) tetramer dissociation to the monomeric intermediate and subsequent polymerization leads to amyloid fibril formation, which is implicated in the pathogenesis of familial amyloid polyneuropathy (FAP) and senile systemic amyloidosis (SSA). Hence, inhibition of fibril formation is considered a potential therapeutic strategy. Here in we demonstrate that curcumin, a phenolic constituent of curry spice turmeric, binds to the active site of TTR through fluorescence quenching and ANS displacement studies. Binding of curcumin appears to inhibit the denaturant induced tertiary and quaternary structural changes in TTR as monitored by intrinsic emission fluorescence and glutaraldehyde cross-linking studies. However, curcumin did not bind to TTR at acidic pH. Protonation/ isomerization of the side chain oxygen atoms of curcumin at low pH might hamper the binding. These results suggest that curcumin binds to and stabilizes TTR thereby highlight the importance of the side chain conformations of the ligand in binding to TTR. 相似文献
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Sharma-Walia N Raghu H Sadagopan S Sivakumar R Veettil MV Naranatt PP Smith MM Chandran B 《Journal of virology》2006,80(13):6534-6552
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Uma Shankar Sagaram Kaoutar El-Mounadi Garry W. Buchko Howard R. Berg Jagdeep Kaur Raghu S. Pandurangi Thomas J. Smith Dilip M. Shah 《PloS one》2013,8(12)
MtDef4 is a 47-amino acid cysteine-rich evolutionary conserved defensin from a model legume Medicago truncatula. It is an apoplast-localized plant defense protein that inhibits the growth of the ascomycetous fungal pathogen Fusarium graminearum in vitro at micromolar concentrations. Little is known about the mechanisms by which MtDef4 mediates its antifungal activity. In this study, we show that MtDef4 rapidly permeabilizes fungal plasma membrane and is internalized by the fungal cells where it accumulates in the cytoplasm. Furthermore, analysis of the structure of MtDef4 reveals the presence of a positively charged γ-core motif composed of β2 and β3 strands connected by a positively charged RGFRRR loop. Replacement of the RGFRRR sequence with AAAARR or RGFRAA abolishes the ability of MtDef4 to enter fungal cells, suggesting that the RGFRRR loop is a translocation signal required for the internalization of the protein. MtDef4 binds to phosphatidic acid (PA), a precursor for the biosynthesis of membrane phospholipids and a signaling lipid known to recruit cytosolic proteins to membranes. Amino acid substitutions in the RGFRRR sequence which abolish the ability of MtDef4 to enter fungal cells also impair its ability to bind PA. These findings suggest that MtDef4 is a novel antifungal plant defensin capable of entering into fungal cells and affecting intracellular targets and that these processes are mediated by the highly conserved cationic RGFRRR loop via its interaction with PA. 相似文献
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Every year about 500,000 people in the United States die as a result of cancer. Among them, 90% exhibit systemic disease with metastasis. Considering this high rate of incidence and mortality, it is critical to understand the mechanisms behind metastasis and identify new targets for therapy. In recent years, two broad mechanisms for metastasis have received significant attention: epithelial-to-mesenchymal transition (EMT) and tumor microenvironment interactions. EMT is believed to be a major mechanism by which cancer cells become migratory and invasive. Various cancer cells--both in vivo and in vitro--demonstrate features of epithelial-to-mesenchymal-like transition. In addition, many steps of metastasis are influenced by host contributions from the tumor microenvironment, which help determine the course and severity of metastasis. Here we evaluate the diverse mechanisms of EMT and tumor microenvironment interactions in the progression of cancer, and construct a rational argument for targeting these pathways to control metastasis. 相似文献