In SilicoScreening of the Library of Pyrimidine Derivatives as Thymidylate Synthase Inhibitors for Anticancer Activity

S. A. Ghone,A. G. Nerkar,A. K. Thaker

doi:10.1155/2009/352717

Abstract

We here report the virtual screening of several series of pyrimidine derivatives forin silicoThymidylate Synthase (TS) inhibition to arrive at possible potential inhibitors of TS with acceptable pharmacokinetic or ADME (Absorption, Distribution, Metabolism and Excretion) properties. Library of the molecules was constructed based upon structural modifications of pyrimidines nucleus. Structural modifications in descending order were performed for the series of pyrimidines,vizfrom pyrimidines with five membered heterocyclic ring to pyrimidines with four membered heterocyclic ring to simple pyrimindine carboxylates in an order to arrive at pyrimidines with better inhibition scores (G-Scores) as compared with Raltitrexed (RTX) and active metabolite of 5-Fluorouracil (5-FUMP). The molecules with betterG-Scores were subjected to predict pharmacokinetic or ADME properties. The molecules with acceptable ADME properties and betterG-Scores were prioritized for synthesis and anticancer evaluation. Three molecules from pyrimidine carboxylate series PIC1-31were found acceptable withG-Scores and pharmacokinetic properties. Thus a library of pyrimidine derivatives was constructed based upon the feasibility of synthesis and in silico screened to prioritize the molecules and to obtain potential lead molecules as TS inhibitors.

Highlights

In silico screening methods such as docking have a great advantage as compared to 2D similarity and 3D pharmacophore search methods as it utilizes the 3D receptor structure in a quantitative way[1]
Structural modifications were carried out on pyrimidines, viz from pyrimidines with five membered heterocyclic ring to pyrimidines with four membered heterocyclic ring and to simple pyrimindine carboxylates in an order to arrive at molecules with better in silico inhibition G-Scores as compared with Raltitrexed (RTX) and active metabolite of 5Fluorouracil (5-FUMP)
RTX was included in the docking run and the same pose as seen in PDB file 1I00 was regenerated confirmed by overlapping method

Summary

Introduction

In silico screening methods such as docking have a great advantage as compared to 2D similarity and 3D pharmacophore search methods as it utilizes the 3D receptor structure in a quantitative way[1]. Structural modifications were carried out on pyrimidines, viz from pyrimidines with five membered heterocyclic ring to pyrimidines with four membered heterocyclic ring and to simple pyrimindine carboxylates in an order to arrive at molecules with better in silico inhibition G-Scores as compared with Raltitrexed (RTX) and active metabolite of 5Fluorouracil (5-FUMP). This generated set of 2000 ligands from series mentioned below viz Series 1 of ligands from 6-Methyl-2-oxo-4-(substituted-phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (4-oxo-2-(substituted-phenyl)-oxazolidin-3-yl)amide, Series 2 of ligands from 6-Methyl-2-oxo-4-(substituted-phenyl)-1,2,3,4-tetrahydro-pyrimidine-5carboxylicacid(4-oxo-2-(substituted phenyl)-imidazolidin-3-yl)amide, Series 3 of ligands from 4-oxo-2-(substituted-phenyl)-thiazolidine-3-carboxylic acid (6-methyl-2-oxo-4(substituted-phenyl)-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide[14], Series 4 of ligands from 3-Chloro-2-oxo-4-(substituted phenyl)-azetidine-1-carboxylic acid (6-methyl-2- oxo-4(substituted phenyl)-1,2,3,4-tetrahydro-pyrimidin-5-yl) amide. RTX and 5-FUMP were included in the ligand sets to give inhibition scores (G-Scores) as compared with these drugs used clinically

C O O C 2H 5 HN

Results and Discussion

Conclusion