118,996 research outputs found
Petrology of andesitic dike and its cognate inclusions from Kuanyinkeng, northern Taiwan
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Studies of glutathione transferase P1-1 bound to a platinum(IV)-based anticancer compound reveal the molecular basis of its activation
No full textPlatinum-based cancer drugs, such as cisplatin, are highly effective chemotherapeutic agents used extensively for the treatment of solid tumors. However, their effectiveness is limited by drug resistance, which, in some cancers, has been associated with an overexpression of pi class glutathione S-transferase (GST P1-1), an important enzyme in the mercapturic acid detoxification pathway. Ethacraplatin (EA-CPT), a trans-PtIV carboxylate complex containing ethacrynate ligands, was designed as a platinum cancer metallodrug that could also target cytosolic GST enzymes. We previously reported that EA-CPT was an excellent inhibitor of GST activity in live mammalian cells compared to either cisplatin or ethacrynic acid. In order to understand the nature of the drug–protein interactions between EA-CPT and GST P1-1, and to obtain mechanistic insights at a molecular level, structural and biochemical investigations were carried out, supported by molecular modeling analysis using quantum mechanical/molecular mechanical methods. The results suggest that EA-CPT preferentially docks at the dimer interface at GST P1-1 and subsequent interaction with the enzyme resulted in docking of the ethacrynate ligands at both active sites (in the H-sites), with the Pt moiety remaining bound at the dimer interface. The activation of the inhibitor by its target enzyme and covalent binding accounts for the strong and irreversible inhibition of enzymatic activity by the platinum complex.Lorien J. Parker, Louis C. Italiano, Craig J. Morton, Nancy C. Hancock, David B. Ascher, Jade B. Aitken, Hugh H. Harris, Pablo Campomanes, Ursula Rothlisberger, Anastasia De Luca, Mario Lo Bello, Wee Han Ang, Paul J. Dyson and Michael W. Parke
Progress in the understanding of drug-receptor interactions, Part 1 : Experimental charge-density study of an angiotensin II receptor antagonist (C30H30N6O3S) at T=17K
No full textAn experimental study of the electron-density distribution rho(r) in an angiotensin II receptor antagonist 1 has been made on the basis of single-crystal X-ray diffraction data collected at a low temperature. The crystal structure of 1 consists of infinite ribbons in which molecules are connected by an N-H center dot center dot center dot N hydrogen bond and several interactions of the CH center dot center dot center dot O, C-H center dot center dot center dot N, and C-H center dot center dot center dot S type. The molecular conformation, characterized by the syn orientation of a tetrazole and a pyrimidinone ring with respect to a phenyl spacer group, is stabilized by two short S center dot center dot center dot O and S center dot center dot center dot N intramolecular contacts between a substituted thiophene fragment and the other two heterocycles of 1. The electrostatic nature of these teractions is documented. Furthermore, the Laplacian of rho(r) in the plane defined by the sulfur, oxygen, and nitrogen atoms involved in these interactions shows their strongly directional character as the regions of charge concentration on the valence shell of the nitrogen and oxygen atoms directly face the regions of charge depletion on the valence shell of the sulfur atom. All the chemical bonds and the relevant intra- and intermolecular interactions of 1 have been quantitatively described by the topological analysis of rho(r). Simple relationships between the bond path lengths (R-b) and the values of rho at the bond critical points (rho(hcp)) have been obtained for the 28 C-C bonds, the seven N-C bonds, and the four O-C bonds. For the first two classes of bonds the relationship is in the form of a straight line, whose parameters, for the C-C bonds, agree, within experimental uncertainty, with those previously derived in our laboratory from a 19 K X-ray diffraction study of crystals of a different compound. Maps of the molecular electrostatic potential phi(r) derived from the experimental charge density display features that are important for the drug-receptor recognition of 1
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