The terminal step of
ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of
DNA ligases in all mammals.
DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of
DNA Ligase I, a therapeutic strategy to impede proliferation of
cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative
DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective
DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked
ligation of nicks on
DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified
Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to
Ligase I, particularly to the
DNA Binding Domain of
Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards
DNA Ligase III and
DNA Ligase IV. Further, addition of
Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in
cancer cells, their proliferation was compromised. Hence, we identify two promising
DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target
cancer cells. © 2016 Wiley Periodicals, Inc.