ИСТИНА

Human tyrosyl-DNA phosphodiesterase 1 (TDP-1) and poly(ADP-ribose)polymerase 1 (PARP-1) are now considered as important therapeutic targets in cancer metabolism. These enzymes repair DNA lesions upon chemotherapy treatment, and their inhibitors can help to overcome drug resistance and promote apoptotic cell death. Here, we report on the results of virtual and experimental screenings for novel competitive TDP-1 and PARP-1 inhibitors. Drug development based on Tdp1 inhibitors is still far from preclinical or clinical stage, and a high-quality molecular model of human Tdp1 accounting for structural features of enzyme's active center is needed to analyze binding sites and interactions with potential ligands. We have constructed such a model taking into account ionization of catalytically important amino acid residues (His263, His493, Lys265, Lys495) and identified substrate-competitive inhibitors by virtual screening of candidate libraries. Several sulfonates were selected and tested in vitro, giving rise to a novel class of inhibitors. A first-in-class PARP-1 inhibitor, olaparib, was recently approved as a treatment for patients with advanced ovarian cancer. Nevertheless, developing effective and non-toxic compounds targeting PARPs and able to suppress the progression of various types of cancers is yet a challenging task. We have assumed that natural compounds might possess better pharmacokinetics and adverse-effect properties compared to synthetic PARP-1 inhibitors and selected a promising new constituent of anticancer therapy, 7-methylguanine. At PARP inhibitory concentration, this natural nucleobase sensitizes BRCA1-deficient breast cancer cells to commonly used chemotherapeutic agents and possesses an attractive QSAR-predicted drug profile.