Homology modeling and in silico screening of inhibitors for the substrate binding domain of human Siah2: implications for hypoxia-induced cancers

• Published in: Journal of molecular modeling 2011-12, Vol.17 (12), p.3325-3332
• Main Authors: Anupriya, Gopalsamy, Roopa, Kothapalli, Basappa, S., Chong, Yap Seng, Annamalai, Loganath
• Format: Article
• Language: English
• Subjects: Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; High-Throughput Screening Assays; Humans; Hydrogen Bonding; Hypoxia - complications; Hypoxia - enzymology; Ligands; Molecular Dynamics Simulation; Molecular Medicine; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - etiology; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Nuclear Proteins - metabolism; Original Paper; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Serine - chemistry; Serine - metabolism; Software; Theoretical and Computational Chemistry; Ubiquitin-Protein Ligases - antagonists & inhibitors; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism; Vitamin K 3 - analogs & derivatives; Vitamin K 3 - metabolism; Vitamin K 3 - pharmacology
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-011-1025-4

The three-dimensional (3D) structure of the substrate binding domain (SBD) of human ubiquitin ligase Siah2 (seven in absentia homolog) was constructed based on the homology modeling approach using the Modeller 9v7 program. The molecular dynamics method was utilized to refine the model and it was further assessed by ProSA, three-dimensional structural superposition (3d-SS) and PROCHEK in order to analyze the quality and reliability of the generated model. Furthermore, we predicted the binding pocket of Siah2 and also validated it by both blind and normal docking using a known functional inhibitor, menadione. Using structure-based high-throughput virtual screening, we identified five lead drug-like molecules against the modeled SBD of Siah2 and analyzed its pharmacokinetic properties to identify the potential inhibitors for Siah2. The docking results for menadione and the lead molecules at the ligand binding site of SBD of Siah2 revealed that the residue Ser39 (corresponding to Ser167 in the full-length protein) is consistently involved in strong hydrogen bonding, and plays an important role in phosphorylation and the enhanced activity of Siah2.