Molecular docking simulations of steroid substrates into human cytosolic hydroxysteroid dehydrogenases (AKR1C1 and AKR1C2): insights into positional and stereochemical preferences

AKR1C1 and AKR1C2 are human cytosolic hydroxysteroid dehydrogenases, which play pivotal roles in the metabolism and action of natural and synthetic steroid hormones. The two enzymes are highly homologous, and have distinct positional and stereochemical preferences with various substrates. We performed molecular docking simulations of three steroid substrates, including an androgen (5alpha-dihydrotestosterone, DHT), a progestin (progesterone, PRO), and a synthetic hormone ([7alpha,17alpha]-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one or tibolone, TIB), into the active sites of the two enzymes. For each substrate and enzyme pair, the activity inferred by the "productive" docking models (in which the spatial arrangement of the steroid and the cofactor would permit a reaction) matched the experimentally observed positional and stereochemical outcome. These productive conformations were energetically and statistically favored except for TIB and PRO with AKR1C2, where experimentally strong substrate inhibition and low activity were observed, respectively. Results showed that (i) a 3-ketosteroid (DHT) and a 20-ketosteroid (PRO) were reduced by AKR1C1 since the carbonyl groups could occupy the same position by "backwards" binding of steroids; (ii) 3alpha-reduced (DHT) and 3beta-reduced (TIB) products were formed by AKR1C2 since the angular methyl groups of the steroids were inverted by "upside-down" binding of steroids; and (iii) the 3beta- and 3alpha-reduction of DHT by AKR1C1 and AKR1C2, respectively occurred since the steroids employed a "swinging" motion to present opposite faces to the cofactor. Favorable nonproductive modes were observed with all substrates in both enzymes in which the steroid was bound at a "near-entry" position and/or an "in-middle" position, which may influence the reaction coordinate.     

Synthesis, characterization and X-ray crystal structure of [Re(L4)(CO)3]Br · 2CH3OH (L4 = N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine): A model compound for novel cationic Tc(I)-tricarbonyl radiotracers useful for heart imaging

This report describes synthesis and evaluation of cationic complexes, [^99mTc(CO)₃(L)]⁺ (L = N-methoxyethyl-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L1), N-[(15-crown-5)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L2) and N-[(18-crown-6)-2-yl]-N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]amine (L3)) as potential radiotracers for heart imaging. Preliminary results from biodistribution studies in female adult BALB-c mice indicated that the cationic ^99mTc(I)-tricarbonyl complex, [^99mTc(CO)₃(L2)]⁺, has a significant localization in the heart at 60 min post-injection. To understand the coordination chemistry of these bisphosphine ligands with the ^99mTc(I)-tricarbonyl core, we prepared [Re(CO)₃(L4)]Br (L4: N,N-bis[(2-diphenylphosphino)ethyl]methoxyethylamine) as a model compound. [Re(CO)₃(L4)]Br has been characterized by elemental analysis, IR, ESI-MS, NMR (¹H, ¹³C, ¹H-¹H COSY, and ¹H-¹³C HMQC) methods, and X-ray crystallography. In solid state, [Re(CO)₃(L4)]⁺ has a distorted octahedron coordination geometry with PNP occupying one facial plane. The chelator backbone adopts a “chair” conformation with phosphine-P atoms at equatorial positions and the amine-N at the apical site. In solution, [Re(CO)₃(L4)]⁺ is able to maintain its cationic nature with no dissociation of carbonyl ligands or any of the three PNP donors.     

The unique alternation of conformationally different (‘chair’-‘saddle’) eight-membered metallocycles [Cd2S4P2] in the chains of cadmium dialkyldithiophosphates: C, P, Cd CP/MAS NMR and single-crystal X-ray diffraction studies

O,O′-Dipropyldithiophosphate and O,O′-dibutyldithiophosphate (Dtph) cadmium(II) complexes were prepared and studied by means of heteronuclear ³¹P, ¹¹³Cd, ³¹C CP/MAS NMR spectroscopy and single-crystal X-ray diffraction. Linear-chain polynuclear structures have been established for both cadmium(II) complexes, in which each pair of equivalent dithiophosphate groups, playing the same bridging structural function, asymmetrically links the neighbouring cadmium atoms. One remarkable structural feature of the synthesised cadmium(II) compounds is defined by the alternation of two types of conformationally different (‘chair’-‘saddle’) eight-membered rings [Cd₂S₄P₂] in the polymeric chains. Therefore, in both ³¹P NMR and XRD data, the bridging dithiophosphate ligands exhibit structural inequivalence in pairs. The structural states of both Dtph ligands and cadmium atoms have been characterised by the ³¹P and ¹¹³Cd chemical shift tensors, which display a profound axially symmetric and mainly rhombic characters, respectively. All experimental ³¹P resonances were assigned to the phosphorus structural sites in both resolved structures.