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E-Journal of Chemistry
Volume 6 (2009), Issue 3, Pages 665-672

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

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

Department of Pharmaceutical and Medicinal Chemistry, School of Pharmacy and Technology Management, SVKM’s NMIMS University, Mumbai-400056, (M.S.), India

Received 29 September 2008; Revised 20 November 2008; Accepted 11 December 2008

Copyright © 2009 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


We here report the virtual screening of several series of pyrimidine derivatives for in silico Thymidylate 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, viz from 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 better G-Scores were subjected to predict pharmacokinetic or ADME properties. The molecules with acceptable ADME properties and better G-Scores were prioritized for synthesis and anticancer evaluation. Three molecules from pyrimidine carboxylate series PIC1-31 were found acceptable with G-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.