Title: Computer-Aided Drug Design for Cancer-Causing H-Ras p21 Mutant Protein
VOLUME: 6 ISSUE: 1
Author(s):Mannu Jayakanthan, Gulshan Wadhwa, Thangavel Madhan Mohan, Loganathan Arul, Ponnusamy Balasubramanian and Durai Sundar
Affiliation:Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, Hauz Khas, New Delhi 110016, India.
Keywords:Molecular docking, H-Ras, Rational drug design, Ras-Raf Interaction, LigandFit, Binding affinity
Abstract: GTP-bound mutant form H-Ras (Harvey-Ras) proteins are found in 30% of human tumors. Activation of H-Ras is due to point mutation at positions 12, 13, 59 and/or 61 codon. Mutant form of H-Ras proteins is continuously involved in signal transduction for cell growth and proliferation through interaction of downstream-regulated protein Raf. In this paper, we have reported the virtual screening of lead compounds for H-Ras P21 mutant protein from ChemBank and DrugBank databases using LigandFit and DrugBank-BLAST. The analysis resulted in 13 hits which were docked and scored to identify structurally active leads that make similar interaction to those of bound complex of H-Ras P21 mutant- Raf. This approach produced two different leads, 3-Aminopropanesulphonic acid (docked energy -3.014 kcal/mol) and Hydroxyurea (docked energy -0.009 kcal/mol) with finest Lipinskis rule-of-five. Their docked energy scores were better than the complex structure of H-Ras P21 mutant protein bound with Raf (1.18 kcal/mol). All the leads were docked into effector region forming interaction with ILE36, GLU37, ASP38 and SER39.
