A Computational Approach towards the Development of Newer Anticancer Agents

In silico molecular docking analyses of the novel 1-(2', 4'dihydroxy-5'-chlorophenyl)-3-aryl-propane-1, 3-diones were performed in the active sites of enzyme cytochrome P450 reductase to obtain new anticancer agents computationally. 1-(2', 4'-dihydroxy-5'-chlorophenyl)-3-(4"-methoxyphenyl)-propane-1, 3-dione (3f) was found to have maximum affinity for the active sites of enzyme.


Introduction
Drug development requires detailed information about the biological activity of the pharmacological compounds against selected targets.The application of computational methods to study the formation of intermolecular complexes has been the subject of intensive research during the last decade.It is widely accepted that drug activity is obtained through the molecular binding of one molecule (the ligand) to the pocket of another, usually larger, molecule (the receptor), which is commonly a protein [1][2][3][4][5][6][7][8][9][10] .
DMBA, an effective carcinogenic initiator, is metabolically activated by cytochrome P450 oxidase to electrophilic diol-epoxide intermediate, which subsequently interact with DNA to form DMBA-DNA adducts [13][14][15][16][17][18] .However the β-diketone functionality in DBM is reduced through the action of liver microsomes, in which cytochrome reductase is thought to be responsible for the reduction.The isolated reductive metabolites of DBM would imply the potential role of DBM as an inhibitor of cytochrome P450 reducatse that is required for the function of cytochrome P450 oxidase to metabolize DMBA, resulting in the inhibitory effect on DMBA-induced mouse mammary tumorigenesis 19 .
.Scheme 1.The said inhibitory effect of DBM on cytochrome P450 reductase provides the root for molecular docking experiments to dock the newly synthesized 1-(2', 4'-dihydroxy-5'chlorophenyl)-3-aryl-propane-1, 3-diones (3a-h) 20 in the active sites of cytochrome P450 reductase and to study the binding affinity.The compound 3a-h was derived from the modification of the initial lead compound DBM (1).Structure 2 shows sites of modification (Scheme 1).

Experimental
The newly synthesized 1-(2', 4'-diydroxy-5'-chlorophenyl)-3-aryl-propane-1, 3-diones (3a-h) endowed with cytochrome P450 reductase inhibition, each compound was energy minimized using the Universal force-field v.1.2and the docking calculations were performed using Argus Lab v 4.0 into the 3D model of the catalytic site of cytochrome P450 reductase enzyme.It should be mentioned that the Lamarckian genetic algorithm (LGA) implemented in Argust Lab has been successfully employed to dock inhibitors into the catalytic site of the cytochrome P450 reductase and to well correlate the obtained binding free energies with inhibitory activities of compounds.Briefly, we carried out comparative docking experiments of synthesized new compound 3a-h with known selective inhibitors of cytochrome P450 reductase such as dibenzoylmethane.The obtained results were evaluated in terms of binding energy and docking poses into the catalytic site of cytochrome P450 reductase.Figure 1

Results and Discussion
The results obtained are given in Table 1.The low binding free energies for the inhibitors means, the high binding affinity, more readily will the inhibitor binds with enzyme in its binding pocket to block its function.The binding free energy for the lead compound dibenzoylmethane is -7.69 and -8.02 kcal/mole using Argus and Genetic algorithms respectively as shown in Table 1.However the binding free energies calculated using Argus and Genetic algorithms for some of the 3a-h viz., 3a, 3c, 3d and 3f are -
compound DBM to inhibit cytochrome P450 reductase and compound 3f found to have maximum binding affinity towards the enzyme.We expressed our sincere thanks to the Head, Department of Chemistry, RMT Nagpur University, Nagpur for providing necessary facilities required to shape out the work.