QSAR Modelling of Thymidylate Synthase Inhibitors in a Series of Quinazoline Derivatives

Abstract

Thymidylate synthase (ThS) is a target for antimetabolite antitumor drugs. Such drugs have been used in the clinic although they cause several severe side effects and accumulate in tissues. Therefore, new less toxic ThS inhibitors must be sought and created. The GUSAR 2013 program was used to study the quantitative structure – activity relationship (QSAR) of a series of antifolate ThS inhibitors in the IC50 range 0.52 – 24,800.00 nM. Statistically significant QSAR models were constructed using MNA- and QNA-descriptors and self-consistent regression. They typically predicted highly accurately the structures of the training and test sets ( $$ {\mathrm{R}}_{\mathrm{train}}^2 $$ : 0.855 – 0.922; $$ {\mathrm{R}}_{\mathrm{train}}^3 $$ : 0.810 – 0.895; $$ {\mathrm{R}}_{\mathrm{test}1}^2 $$ : 0.734 – 0.790; $$ {\mathrm{R}}_{\mathrm{test}2}^2 $$ : 0.800 – 0.835).