title: 3D Structure Generation, Molecular Dynamics and Docking Studies of IRHOM2 Protein Involved in Cancer & Rheumatoid Arthritis.
abstract: A short-lived membrane protein IRHOM2 pedals a cascade of events by regulating Epidermal Growth Factor Receptor (EGFR) signalling in parallel with metalloproteases which results their involvement in cancer as well as in rheumatoid arthritis. Therefore, IRHOM2 is a potential therapeutic drug target for these diseases, but its 3D-structure has not been reported yet. In this study, the three-dimensional structure of the IRHOM2 protein was generated using I-TASSER (Iterative Threading Assembly Refinement) server. The modeled structure of IRHOM2 receptor was validated using various Structural Analysis and Verification Server (SAVES) in which 99.7% of amino acid residues are present in the favoured regions of the Ramachandran Plot. Further, the refined modeled structure was subjected to molecular dynamics simulation & docking analysis. Virtual screening studies were carried out using Glide with various selective libraries containing 24552 compounds and the analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a significant role in its binding. Docking results were analyzed for high ranking compounds using a consensus based docking score to calculate the binding affinity as a measure of protein-ligand interactions. The top ranking molecule against IRHOM2 active site has a glide g-score of -12.565 kcal/mol and glide e-model score of -74.967 with 3 hydrogen bonds and 11 hydrophobic contacts. This compound may act as probable inhibitor against these chronic diseases but further in vitro studies are required.
authors.forename: Utkarsh
authors.initials: U
authors.lastname: Raj
authors.forename: Himansu
authors.initials: H
authors.lastname: Kumar
authors.affiliation: Department of Bioinformatics, Indian Institute of Information Technology, Allahabad, Allahabad-211012, India. pritish@iiita.ac.in.
authors.forename: Pritish Kumar
authors.initials: PK
authors.lastname: Varadwaj
mesh_terms: D000595:Amino Acid Sequence; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C580845:RHBDF2 protein, human; D054852:Small Molecule Libraries