Binding Energy Of Compounds Obtained From Chembank

Published Date: 02 Nov 2017

ABSTRACT

INTRODUCTION

P53 mutation is the most common mutation in human cancer .p53 is triggered by genotoxic effects which lead to stabilization, modification of the post transcriptional processes and recruitment to chromatin. Being a transcription factor it mediates change is gene expression that decided the cell fate for survival by arresting the cell cycle for repair or death via apoptosis. But mutations in p53 makes the cell susceptible for with somatic or germ line cancer. Many of these mutant p53 proteins acquire oncogenic properties that enable them to promote invasion, metastasis, proliferation and cell survival. Around 75% of p53 mutations are in the DNA binding domain and about 30% are in the hotspot codon regions. [1]These mutations are associated with the DNA binding domain thermo-stability to varying degrees. [2] Amino acids that are involved in the recognition of specific sequences of the DNA. Some mutations affect distant sites cause defects in the conformation of p53 rendering it inactive. If its native intact form is lost by mutations of single nucleotide, p53 activity is lost. [2]

P53 is one of ideal candidate for designing a drug for cancer therapy. The function of p53 can be restored by stabilizing the destabilized active conformation of mutants. This is achieved by identifying low molecular weight compounds by high throughput screening of chemical libraries. Several approaches for identification of small molecules that target mutant p53 have been applied, including rational design and screening of chemical libraries. These molecules can serve as lead compounds as novel efficient anti cancer drugs. Since many tumors express elevated levels of p53, restoring the p53 wild-type function would help in killing tumor cells by inducing apoptotic pathways in tumors. Restoring p53 activity may not only lead to discovery of more potent analogs but may also suggest new strategies for p53-targeting in tumor therapy. The compound PhiKan083 binds with high affinity to a crevice created by the Y220C mutation in p53 and stabilizes the mutant protein. The compound PRIMA-1 (p53 reactivation and induction of massive apoptosis) restores wild-type conformation to mutant p53 by binding to the core and induces apoptosis in human tumor cells. The PRIMA-1 analog APR-246 is currently tested in a clinical trial.[6]

MATERIAL AND METHODS

In silico screening

500 molecules were screened from Chemical databases including PubChem and ChemBank. They were docked into the active site Val 147 of mutant p53 (PDB id: 2X0W)[4] using the AutoDock4.[3]

Substrate selection

Firstly top 25 drug structures most 2D-similar to 1-hydroxy-2-methylanthraquinone were chosen based on screening from the ChemBank and PubChem. These ligands have conformational as well as structural diversity in relation to bound ligands of the 1-hydroxy-2-methylanthraquinone crystal structure. Solubility and pharmacokinetic parameter helped in identifying these ligands. The active site Valine 147 in the protein interacts with the ligands of the substrate and gives rise to catalytic activity to test ligands which helps in determining the binding pattern of the ligand to the active site of mutant p53 (PDB id: 2X0W)

A B

Figure 1: Structures of 1-hydroxy-2-methylanthraquinone

A: 2D Structure

B: 3D Conformer

Compound Information Descriptors

Molecular Formula

C15H10O3 

Molecular Weight

238.2381

IUPAC Name

1-hydroxy-2-methylanthracene-9,10-dione

InChI

1S/C15H10O3/c1-8-6-7-11-12(13(8)16)15(18)10-5-3-2-4-9(10)14(11)17/h2-7, 16H, 1H3

InChIKey

CZODYZFOLUNSFR-UHFFFAOYSA-N

Canonical SMILES

CC1=C(C2=C(C=C1)C(=O)C3=CC=CC=C3C2=O)O

Also known as

Anthraquinone, 1-hydroxy-2-methyl-, CCRIS 6433, CHEBI:69534, 6268-09-3, 1-hydroxy-2-methylanthracene-9,10-dione, NSC37131, AC1L4OAX

The molecules were searched by similarity search compound collection, by similarity to a structure (may be specified via a SMILES string, or drawn with JME Molecular Editor). The molecules were screened where the structure is similar to CC1=C(C2=C(C=C1)C(=O)C3=CC=CC=C3C2=O)O (of 1-hydroxy-2-methylanthraquinone from PubChem) using the Tanimoto metric with a distance of .8.

2.3 Docking setup

Docking was performed using Autodock 4, which combines energy evaluation through grids of affinity potential employing various search algorithms to find the suitable binding position for a ligand on a given protein.[3] While docking, polar hydrogen’s were added to ligands using the hydrogen’s module in Autodock tool and thereafter, Kollman united atom partial charges were assigned. [(La Motta et al., 2007)] Docking of mutant p53 to ligands was carried out using LGA with standard docking protocol on the basis a population size of 150 randomly placed individuals; a maximum number of 2.5 *107 energy evaluations, a mutation rate of 0.02, a crossover rate of 0.80 and an elitism value of 1. Fifteen independent docking runs were carried out for each ligand and results were clustered according to the 1.0 Ǻ rmsd criteria. The grid maps representing the proteins were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. The coordinate of the docked protein along with the ligand was visualized using UCSF chimera within 6.5 Ǻ region. [5]

RESULTS AND DISCUSSION

Docking studies was carried out on p53 core domain mutant Y220C showed a minimum binding energy in the range of - 15.09 kcal/mol to -12.2 kcal/ mol. On docking of 500 molecules with Val147 (as an active site) residue according to the minimum binding energy generated by autodock4 the best results were shown by following compounds.

Table1: Binding Energy of Compounds obtained from ChemBank