Abstract
Testicular cancer develops in one or both of the testicles in young men. Rab8b is a member of the Rab small G protein family, participates in intracellular trafficking events at the site of the adherence junction dynamics in the testis. Overexpression of Rab8b and loss of functioning adherence junction accelerates the tumorigenesis in testis. In the present work, the computer aided high throughput virtual screening studies are applied to identify potent leads for human Rab8b protein. The homology model of Rab8b of 207 amino acid residues chain length was evaluated based on the crystal structure of an appropriate template, and reveals the presence of 6 α-helices and 6 β-strands. The energy of the generated model was minimized and the model was validated using ProSA PROCHECK and ERRAT server tools. The active site was identified using the computational binding site prediction tools like CASTp, efindsite seversand Sitemap of Schrodinger, which show that the residues (GLU33 to GLN60) are important for binding. The molecular interactions of Rab8b with its natural substrate Rabin 8, were examined by in silico protein-protein docking studies using patchDock tool, and the results were corroborated with the active site identified from the computational tools. Virtual screening studies were carried out with ligand databases using Glide docking program of Schrodinger suite. The ligands obtained from XP docking with high Glide score and Glide energy, were subjected to QikProp module to predict their ADME properties. These ligands, based on the pharmacokinetic properties, which are new entities, were considered as novel potent inhibitors in cancer therapy.
Highlights
The uncontrolled proliferation and growth of the cells leads to cancer [1,2]
Homology models of Rab8b, using Modeller 9.11, were built. 25 models were initially considered based on comparative protein structure modeling protocols, satisfying the spatial restraints in terms of probable density function [52]
Our study provides the 3D structure of Rab8b with 207 amino acid residues through homology modeling approach
Summary
The uncontrolled proliferation and growth of the cells leads to cancer [1,2]. Testicular cancer affects young men, and has one of the highest cure rates of all cancers with an average five-year survival rate of 95% [3]. Rabs are signaling proteins of approximately 20 kDa, constituting the largest family of monomeric GTPases that localize on the cytoplasmic surfaces of distinct membrane-bound organelles [4]. Their function in diverse intracellular pathways such as vesicular trafficking, polarized transport of proteins, and cell movement depends on their ability to shuttle between GTP (an active form, membraneassociated)-bound and GDP (an inactive form, cytosol-associated)bound conformations. Rab8b, which represents a novel class of cellular modulators that affects both initiation and progression of tumor cells in Homo sapiens, is treated as a novel target for design of new leads against testicular cancer
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have