Stabilizing p53 mutant Y220C by 1-hydroxy-2-methylanthraquinone and its derivative: a virtual screening, molecular docking and ADMET study
V. Ahire, G R. Kulkarni, Kaushala P Mishra, S.A.H. Naqvi
p53, as a transcription factor, plays an eminent role in tumor suppression. Y220C, a substitution mutation, which cause major structural changes in the protein, is evidenced to form a new protein cavity. This cavity is reckoned to accommodate small drug candidates, which may play a key role in cancer suppression. In the present, study we have tried to determine a drug candidate based on structural drug discovery. Docking simulation on mutated p53 was performed to determine the best drug candidate from the derivatives of 1-hydroxy-2-methylanthraquinon, a known anti-cancer agent. A total of 479 structures had been selected on the basis of molecular fingerprinting towards the 2D crystal structure of 1-hydroxy-2-methylanthraquinone. With a combination of tools and knowledge based method the cavity had been tested for identification of an accurate position vector for molecular docking studies. Molecular Docking was simulated and study has been carried out by using Lamarckian Genetic Algorithm (LGA), a novel conformational search strategy. MGL's Auto Dock 4 which have a free energy scoring function, based on linear regression and uses the AMBER force field for optimization, have been used for Docking studies. The post-docking studies had confirmed fluctuating binding energies along with a few cases (~14%) of structural damage and possible fragmentation. The minimum binding free energy had been recorded within a range between -15.09 and -4.88 kCal/mol. Our studies conform the binding of ligand at the active site cavity as hydrogen bonds and polar contacts between the ligand and the protein cavity.
V. Ahire, G R. Kulkarni, Kaushala P Mishra, S.A.H. Naqvi. Stabilizing p53 mutant Y220C by 1-hydroxy-2-methylanthraquinone and its derivative: a virtual screening, molecular docking and ADMET study. European Journal of Biotechnology and Bioscience, Volume 1, Issue 6, 2014, Pages 01-09