Insilico modeling and analysis of small molecules binding to the PHLPP1 protein by molecular dynamics simulation.

The PHLPP (Pleckstrin homology domain leucine-rich repeat protein phosphatases) is a newly discovered group of genes which includes PHLPP1 and PHLPP2 and plays an integral part in several cellular processes like apoptosis, cell signaling cell survival, and cell proliferation etc. Both the activation and deactivation of these genes can have vital role in several ailments like heart diseases, circadian rhythm and most importantly the cancer, hence encouraging the growth of novel therapeutic elements. To give new directions into the development of PHLPP1- targeting drugs, the interaction mechanism between PHLPP1 and five important ligands 4IP, B39, 635, ATP and GTA were investigated through docking and Molecular Dynamics Simulation. It is also noteworthy to be mentioned here that there is no previous crystal structure of PHLPP1 available. The in-silico results can provide potential base for advancements in development of new therapeutic elements targeting different diseases, mainly cancer. In this study, we employed homology modeling technique to develop a high-quality structure model of PHLPP1. The PHLPP1 model was then used in docking interaction analysis and Molecular Dynamics Simulation, to study binding pockets and interactions of PHLPP1 ligands and finding actively contributing residues in binding pocket. In final step, Free Energy Estimation was performed to observe ligand binding's quantitative characteristics.

Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene.

Single Nucleotide Polymorphisms (SNPs) are the most common candidate mutations in human beings that play a vital role in the genetic basis of certain diseases. Previous studies revealed that Solute Carrier Family 26 Member 4 (SLC26A4) being an essential gene of the multi-faceted transporter family SLC26 facilitates reflexive movement of Iodide into follicular lumen through apical membrane of thyrocyte. SLC26A4 gene encodes Pendred protein, a membrane glycoprotein, highly hydrophobic in nature, present at the apical membrane of thyrocyte functioning as transporter of iodide for thyroid cells. A minor genetic variation in SLC26A4 can cause Pendred syndrome, a syndrome associated with thyroid glands and deafness. In this study, we performed in-silico analysis of 674 missense SNPs of SLC26A4 using different computational platforms. The bunch of tools including SNPNEXUS, SNAP-2, PhD-SNP, SNPs&GO, I-Mutant, ConSurf, and ModPred were used to predict 23 highly confident damaging and disease causing nsSNPs (G209V, G197R, L458P, S427P, Q101P, W472R, N392Y, V359E, R409C, Q235R, R409P, G139V, G497S, H723R, D87G, Y127H, F667C, G334A, G95R, S427C, R291W, Q383H and E384G) that could potentially alter the SLC26A4 gene. Moreover, protein structure prediction, protein-ligand docking and Molecular Dynamics simulation were performed to confirm the impact of two evident alterations (Y127H and G334A) on the protein structure and function.