Kanserde biyolojik olarak önemli hedefler için küçük molekül inhibitörler saptamak

In this thesis, we investigated plant secondary metabolites as potential drugs for cancer and identified plant based small molecule inhibitors for biologically important targets by screening a plant based library that we constructed. We carried out two projects and developed new methods for this purpose.In the first part, we aimed to inhibit base excision repair (BER) pathway that is the major system for correcting many types of oxidative DNA damages and mono functional base modifications caused by endogenous and exogenous agents including chemotherapeutics. Whereas DNA repair pathways mediate resistance to DNA damage and protect the cells from its killing effects, and maintain genomic stability, inhibition of DNA repair pathways is required for the toxicity of several anticancer drugs and ionizing radiation. Because the cytotoxic effects of most chemotherapeutic agents and radiation are related to their ability to induce DNA damage. The DNA repairing system of cancer cells is therefore disadvantageous to cancer treatment. We identified plant based small molecule inhibitors for two critical BER proteins, mitochondrial DNA polymerase ? and nuclear DNA polymerase ß as potential therapeutic targets to sensitize tumors. We found an inhibitor for known active site of polymerase ß with more significant interactions than found in previous studies. We also identified three promising inhibitors for polymerase ? targeting a specific interface of polymerase ? for the first time in literature.In the second part, we investigated plant secondary metabolite specificities on three biologically important domains, PDZ, BROMO and SPRY, which have high drug target potency for a large variety of diseases including cancers. Interest in molecular target-class specificity information is getting increased due to the advantages into drug design. However, studies about information on molecular targets are lacking systematic methods to identify the specificities. We developed a novel method that will enable to analyze and identify the domain-class specificity more quantitatively and for this purpose we used the Gibbs Distribution of binding energies in order to differentiate different ligands. We identified three specific plant secondary metabolite classes, Triterpenoids, Stilbenoids and Stereoidal alkaloids for PDZ, BROMO and SPRY domains, respectively.