Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11β-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1

Analysis of lateral loading of pile groups using embedded beam elements with interaction surface

The numerical simulation of soil-pile interaction problems, by means of full 3Dfinite element models, involves a large number of degrees of freedom (DOF)and difficulties during the mesh generation process. In order to reduce theunknowns and simplify and properly analyze such class of geotechnical prob-lems, the so-called embedded beam elements (EBE) have recently been devel-oped. In a preceding contribution of the authors, an improved EBE formulation,which brings into play the soil-pile interaction surface, was proposed with theaim to localize material plasticity in the soil surrounding the pile. This embed-ded beam model couples two different finite elements, each described by distinctkinematics (ie, solid and beam). The coupling is incorporated in the formulationby means of kinematical constrains established over the solid and beam dis-placement fields on the interaction surface. One of the main advantages of theembedded elements is that the addition of beams structural members immersedwithin the 3D soil model does not represent a constraint for the solid mesh,which can be adopted independently from the beam mesh. In this paper, the lat-eral loading of pile groups is studied by means of the proposed EBE approachwith elasto-plastic interfaces. In order to represent a rigid cap, a master node anda special set of kinematical restrictions are incorporated into the formulation.The paper presents results obtained by means of the present formulation com-pared against other well-established analysis methods and test results publishedin the literature, for both elastic and elasto-plastic cases.Fil: Turello, Diego Fernando. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pinto, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones en Química Biológica de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Centro de Investigaciones en Química Biológica de Córdoba; ArgentinaFil: Sánchez, Pablo Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Centro de Investigaciones en Métodos Computacionales. Universidad Nacional del Litoral. Centro de Investigaciones en Métodos Computacionales; Argentin