This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cancer cells rely more heavily on the de novo purine biosynthetic pathway than normal cells, which favor the salvage pathway as their main purine source. The main enzymatic targets in the de novo pathway for potential anti-cancer drug(s) are two folate-dependent transformylases, glycinamide ribonucleotide transformylase (GAR Tfase) and amino-imidazole carboxamide ribonucleotide transformylase (AICAR Tfase). The GAR Tfase structure was solved over a decade ago; however, the enzyme has many flexible loops in its active site that has compounded the problem of structure-based drug design and elucidation of its reaction mechanism. A recent fluorofolate complex structure has revealed that this complex seems to most closely represent the active state structure. A comprehensive comparative AutoDock study validated this new structural template for our continuing efforts on structure-based drug design. Our more recently determined AICAR Tfase structure presents a new target. In some ways it will be a better target because its kinetics are pH-independent and it has a relatively rigid active site. AICAR Tfase inhibitors also have potential use in treatment of inflammatory diseases, such as rheumatoid arthritis. On the other hand, it is highly desirable to discover alternative structural scaffold(s) to design a new generation of specific inhibitors, not just the traditional antifolates, We already used AutoDock to virtually screen the pharmacophore-representative NCI Diversity Set by utilizing NCRR/NBCR and Scripps sponsored computing clusters.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR008605-14
Application #
7601657
Study Section
Special Emphasis Panel (ZRG1-SSS-9 (40))
Project Start
2007-05-01
Project End
2008-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
14
Fiscal Year
2007
Total Cost
$8,862
Indirect Cost
Name
University of California San Diego
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Pantoja, Joe Luis; Morgan, Ashley E; Grossi, Eugene A et al. (2017) Undersized Mitral Annuloplasty Increases Strain in the Proximal Lateral Left Ventricular Wall. Ann Thorac Surg 103:820-827
Morgan, Ashley E; Wozniak, Curtis J; Gulati, Sarthak et al. (2017) Association of Uneven MitraClip Application and Leaflet Stress in a Finite Element Model. JAMA Surg 152:111-114
Morgan, Ashley E; Pantoja, Joe L; Grossi, Eugene A et al. (2016) Neochord placement versus triangular resection in mitral valve repair: A finite element model. J Surg Res 206:98-105
Purvine, Emilie; Monson, Kyle; Jurrus, Elizabeth et al. (2016) Energy Minimization of Discrete Protein Titration State Models Using Graph Theory. J Phys Chem B 120:8354-60
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Ebeida, Mohamed S; Rushdi, Ahmad A; Awad, Muhammad A et al. (2016) Disk Density Tuning of a Maximal Random Packing. Comput Graph Forum 35:259-269
Yang, Pei-Chi; Boras, Britton W; Jeng, Mao-Tsuen et al. (2016) A Computational Modeling and Simulation Approach to Investigate Mechanisms of Subcellular cAMP Compartmentation. PLoS Comput Biol 12:e1005005
Watson, Shana R; Liu, Piaomu; Peña, Edsel A et al. (2016) Comparison of Aortic Collagen Fiber Angle Distribution in Mouse Models of Atherosclerosis Using Second-Harmonic Generation (SHG) Microscopy. Microsc Microanal 22:55-62
Ge, Liang; Wu, Yife; Soleimani, Mehrdad et al. (2016) Moderate Ischemic Mitral Regurgitation After Posterolateral Myocardial Infarction in Sheep Alters Left Ventricular Shear but Not Normal Strain in the Infarct and Infarct Borderzone. Ann Thorac Surg 101:1691-9
Morgan, Ashley E; Pantoja, Joe Luis; Weinsaft, Jonathan et al. (2016) Finite Element Modeling of Mitral Valve Repair. J Biomech Eng 138:021009

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