Structure-based design of anticancer prodrug PABA/NO

Abstract

Poster Sessions structures and discuss further design strategies for highly selective family 3 glycoside hydrolase inhibitors.Keywords: glycosyl hydrolases, antibiotic resistance, structure-based drug design P04.15.355Acta Cryst. (2008). A64, C342The crystal structure of AKR1C1 in complex with an active-site inhibitor Hydroxysteroid dehydrogenases (HSDs) regulate a wide range of physiological processes including reproduction, development and homeostasis. AKR1C1, is a 20α-HSD involved in the conversion of progesterone to 20-hydroxyprogesterone. Increased activity of AKR1C1 in the endometrium and in breast tissues leads to the formation of tumor-promoting metabolites and to the development of endometriosis, breast cancer and endometrial cancer. At present, there are few known inhibitors that specifically bind and inhibit the adverse actions of AKR1C1. Here we present the first crystal structure of AKR1C1 in complex with potent inhibitor 3,5-dichlorosalicylic acid (IC50 = 44 nM). The crystal structure was solved at a resolution of 1.8 Å, with clear electron density corresponding to the inhibitor bound in the active site. The details of the enzyme-inhibitor interactions and selectivity against members of the AKR1C subfamily will also be discussed. The structural information obtained from this study will help speed up the drug design process for the development of more selective and potent compounds that can be used in the treatment of endometriosis and cancer. Eimeria species are parasitic Apicomplexa protozoans that cause gastrointestinal coccidiosis infections in birds, and are associated with general morbidity and intestinal lesions. These parasitic infections lead to major losses within the broiler industry, a situation that is deteriorating due to emerging resistance to available therapeutics. By analogy with other Apicomplexa obligate parasites, in the intracellular stages of its lifecycle the Eimeria parasite relies heavily on glycolysis for ATP production, and hence on homolactic fermentation -the action of lactate dehydrogenase (LDH) -to restore the NADH/NAD + balance. These parasites are therefore extremely sensitive to LDH inhibition. In common with the LDH of the malaria causing parasite Plasmodium falciparum (PfLDH), Eimeria tenella LDH (EtLDH) has a characteristic five amino acid insert in a loop directly adjacent to the active site. As a consequence, we reasoned that compounds we have previously designed to specifically inhibit PfLDH should cross-react with EtLDH. We are therefore undertaking crystallisation and structural analysis of EtLDH and its inhibitory complexes in order to explore the possibility of targeting EtLDH for novel veterinary therapeutics. HU is an architectural protein for bacterial chromosome compaction and organization.HU is one of the most ubiquitous proteins in the bacterial cell.It is a small basic protein, binding non-specifically throughout the nucleoid. While the sequence of HU is highly conserved through most of the bacterial species, the HU in M.tuberculosis has a sequence...

Growth‐inhibitory and chemosensitizing effects of the glutathione‐S‐transferase‐π‐activated nitric oxide donor PABA/NO in malignant gliomas

“…This negative regulatory control of MAPK pathways by GST-π may be overcome by NO released from PABA/NO. Chemosensitization to TMZ by PABA/NO can be attributed to a variety of effects including arylation of GSH, S-nitrosylation of GST, inhibition of DNA synthesis, generation of toxic RNS/ROS and inhibition of DNA repair by NO-induced interaction with DNA repair enzymes 17,40 .…”

Nitric Oxide (NO) Releasing Poly ADP-ribose Polymerase 1 (PARP-1) Inhibitors Targeted to Glutathione S-Transferase P1-Overexpressing Cancer Cells

“… 25 Briefly, the initial models of the Meisenheimer complex of compound 13 (GS 13 – ) bound to GSTP1 or GSTA1 was built on the basis of the GSTCD – in the GSTP1·GSTCD – structure (PDB entry 1AQX) 26 or in the GSTA1·GSTCD – model complex. 25 The initial GSTA1·GSTCD – model complex was built on the basis of the crystal structures of the GSTCD – found in the active sites of GSTM1 (PDB entry 4GST) and GSTP1 (PDB entry 1AQX), and then it was docked into the active site of GSTA1 in complex with the GSH adduct of ethacrynic acid (PDB entry 1GSE). The GSTP1·GS 13 – and GSTA1·GS 13 – complexes built in dimeric forms because GSH interacts with the side chains from both subunits of GST.…”

Novel insights into conjugation of antitumor-active unsymmetrical bisacridine C-2028 with glutathione: Characteristics of non-enzymatic and glutathione S-transferase-mediated reactions

“…For the enzymatic synthesis of GSH S-conjugate of C-2028, we postulate the GST-catalyzed nucleophilic aromatic substitution with GSH. This reaction pathway is quite common for many GST substrates [ [33] , [34] , [35] ]. It is also interesting to note that the mechanisms of GST-mediated conjugations and reductions are extremely variable and highly depend on the GST class and on the substrate [ 9 ].…”