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| About Yulia Borodina (NCBI) |
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Dr. Yulia V. Borodina obtained her Ph.D. in 1998 at the Institute of Biomedical Chemistry of the Russian Academy of Medical Sciences (RAMS) in biochemistry with a thesis on “Computer-Based Analysis of Chemicals’ Similarity with Endogenous and Synthetic Bioregulators.” Thereafter, she worked through 2004 as a Scientist at the same institute in the Laboratory for Structure-Function Based Drug Design on projects involving development and evaluation of a computer program for predicting receptor profiles for drug-like compounds; chemical similarity analysis for substrates of cytochrome P450 isoforms; clustering of enzyme families by structural similarity of substrates and application of this to cytochromes P450 and serine proteases; and computer-aided prediction of the cytochrome P450 metabolism profile for drug-like compounds. Since 2004, she has been a Postdoctoral Fellow at the National Center for Biotechnology Information (NCBI), National Library of Medicine (NLM), NIH, working on methodology for the generation of 3D conformational models of small molecules and questions of conformational coverage of such models.
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Reproduction of PDB Ligand Structures by Conformational Ensembles at Different Energy Thresholds
Yulia Borodina (NCBI)
The reproduction of PDB ligand conformations by conformational ensembles obtained using low energy thresholds is compared to the reproduction by equal-sized ensembles selected randomly from the initial ensemble. The initial ensembles were created by applying a 100kcal/mol energy limit in the MMFF94s force-field, using Omega 2.2 (OpenEye Scientific Software, Inc) 3D-models and a Monte-Carlo conformer generation procedure followed by optimization of the internal coordinates while holding torsion angles fixed. The ensembles were subsequently enriched with low energy conformers by adding partly and fully optimized conformers. Optimizations and global energy minimum calculations were done using the CASE toolkit (OpenEye Scientific Software, Inc). The quality of reproduction of a PDB structure was estimated by the minimum RMSD found between any of the ensemble’s conformers and the X-ray structure (RMSD-Xray). The data set used for the study consists of ca. 2000 bioligands extracted from the PDB under the following constraints: Crystallographic resolution of 2.0Å or better, average ligand B-factor of 50Å2 or lower, and number of rotatable bonds 6 or less. RMSD-Xray averaged over compounds of equal flexibility was used as the criteria of the average reproduction quality. To validate the methodology, several test sets of ligand ensembles with conformations modeled by a force field approach within specific energy ranges were subjected to the same approach. We report on the presence or absence of significant improvement of RMSD-Xray as a function of the energy threshold in the range of 1-40 kcal/mol when compared with the same-size random ensembles, for each ligand subset of a certain flexibility range. Initial results suggest that some PDB ligand conformers have relatively high energy and cannot be reproduced by conformations created with thresholds of a few kcal/mol.
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