Publications & Presentations

  1. Macherone, AJ “High-Throughput NMR Analysis: The End Game”. ACD/Labs NJ NMR Seminar 2007. October 11, 2007, New Brunswick, NJ
  2. Wagaman, Michael W.; Smith, Garry R.; Blize, Alan E. "Design, synthesis and purification of diverse lead-like libraries"ACS Abstracts, 234th National Meeting, 2007, Abstract 807, Boston, MA.
  3. Smith, Garry R.; Wagaman, Michael W.; Blize, Alan E. "Synathesis of substituted azaindoles and their lead-like libraries", ACS Abstracts, 234th National Meeting,  2007, Abstract 795, Boston, MA.
  4. Wagaman, Michael W.; Smith, Garry R.; Blize, Alan E. “Design and Synthesis of Diverse Lead-Generation Libraries” CHI Drug Discovery Chemistry Conference, 2007 La Jolla, CA.
  5. Hu, X.; Addlagatta, A.; Mathews, B.W.; Liu, J.O. ”Identification of Pyridinylpyrimidines as Inhibitors of Human Methionine Aminopeptidases” Angew. Chem. Int. Ed. 2006, 45, 3772.
  6. Chen, X.; Chong, C.R.; Shi, L.; Yoshimoto, T.; Sullivan, D.J. Jr.; Liu, J.O.  “Inhibitors of Plasmodium falciparum methionine aminopeptidase 1b possess antimalarial activity”  PNAS2006, 103(39), 14548-14553.
  7. Macherone, AJ. “A LC-UV-MS "Method and Validation Procedure to Analyze Diverse Chemical Compounds using a Sub-two Micron Particle Size Column” 9th Annual Symposium on Chemical and Pharmaceutical Structure Analysis. October 17 - 19, 2006. Princeton, NJ.
  8. Downes, S., Macherone, AJ. “An Application of A Priori Methodology In Early Drug Discovery” 28th Annual Ion Chemistry Conference, September 30, 2006. Brown Labs, University of Delaware. Newark, DE.
  9. Macherone, AJ. “Rapid LC-MS Method for High Throughput Analysis of Drug-Like Compounds” 231st Meeting of the American Chemical Society. March 26 - 30, 2006. Atlanta, GA.
  10. Macherone AJ. “Standard C18 column in high throughput LC-MS applications” Separation Methods Technologies Application Note, 2006.
  11. Macherone AJ. “Spot Chek™ Computer Aided Thin-Layer Chromatography System” 57th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy, March 12-17, 2006. Orange County Convention Center. Orlando, FL.
  12. Macherone, AJ. “A priori screening of large and diverse chemical libraries” 8th Annual Symposium on Chemical and Pharmaceutical Structure Analysis, October 17 - 20, 2005. Princeton, NJ.
  13. Macherone, AJ, Wagaman, MW, Kates, M, Smith GR, Houseknecht, K. An Example of the Fragonomics Paradigm. World Pharmaceutical Congress. Biochemical-based Assays for HTS: Maximizing Quality, Efficiency and Information Content. May 13-14, 2008 • Loews Philadelphia Hotel • Philadelphia, PA
  14. Wagaman, MW, Macherone, A. Repurposing Compound Collections for New Drug Discovery Paradigms. 235th Meeting of the American Chemical Society, April 6-10, 2008. New Orleans, LA,
  15. Macherone, A. Wagaman, MW. Comparison of Calculated Aqueous Solubility and Permeability to Experimental Data for a Fragment Based Screening Set. 235th Meeting of the American Chemical Society, April 6-10, 2008. New Orleans, LA
  16. Macherone, AJ (Invited Speaker). The Eclectic NMR: High-throughput Support of Multi-disciplinary Services. 49th Experimental Nuclear Magnetic Conference. March 9 – 14, 2008. Asilomar Conference Grounds. Pacific Grove, CA
  17. Macherone, AJ (Invited Speaker). Column Technology for High Throughput LC-MS Analysis of Drug-Like Compounds: Monolithic Silica vs. Agilent Eclipse XDB-C18 RRHT 4.6x15mm, 1.8micron Packing Materials. Agilent Winter Webinar Series 2007
  18. Macherone, AJ (Invited Speaker) High-Throughput NMR Analysis: The End Game. ACD/Labs NJ NMR Seminar 2007. October 11, 2007, New Brunswick, NJ
  19. Macherone, AJ. A LC-UV-MS Method and Validation Procedure to Analyze Diverse Chemical Compounds using a Sub-two Micron Particle Size Column. 9th Annual Symposium on Chemical and Pharmaceutical Structure Analysis. October 17 - 19, 2006. Princeton, NJ
  20. Downes, S., Macherone, AJ. An Application of A Priori Methodology In Early Drug Discovery. 28th Annual Ion Chemistry Conference. September 30, 2006. Brown Labs, University of Delaware. Newark, DE
  21. Macherone, AJ. Rapid LC-MS Method for High Throughput Analysis of Drug-Like Compounds. 231st Meeting of the American Chemical Society. March 26 - 30, 2006. Atlanta, GA
  22. Macherone AJ. Standard C18 column in high throughput LC-MS applications. Separation Methods Technologies, Inc. Application Note. http://www.separationmethods.com
  23. Macherone AJ. Standard C18 column in high throughput LC-MS applications. 57th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy. March 12-17, 2006. Orange County Convention Center. Orlando, FL
  24. Macherone AJ. Spot Chek™ Computer Aided Thin-Layer Chromatography System. 57th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy. March 12-17, 2006. Orange County Convention Center. Orlando, FL
  25. Macherone, AJ. A priori screening of large and diverse chemical libraries. 8th Annual Symposium on Chemical and Pharmaceutical Structure Analysis. October 17 - 20, 2005. Princeton, NJ

Abstracts

2 Abstract:  Compound libraries generated by parallel synthesis often suffer from either insufficient diversity, such that all compounds are nearly identical, or too much diversity, so that hit verification can be time consuming and costly.  These libraries respectively risk missing potentially valuable hits outside of a narrowly defined compound space, or risk identification of false positives where expensive follow-up studies are fruitless.

Our research has focused on addressing these problems through the design of libraries that incorporate both wide diversity and also clusters of sufficiently similar compounds to allow immediate hit verification.  Through the course of this research we have identified methods to balance the desire to maximize the utility of these libraries while keeping the chemical synthesis requirements reasonable.  Due to the inherent diversity of the libraries, some unexpected synthesis and purification challenges were encountered and then overcome using a variety of standard and novel approaches.

3 Abstract:  Recent popularity aside, azaindoles have been under-represented in drug discovery research.  While these compounds have clear physiochemical advantages versus indoles, they have suffered due to a lack of commercially available representatives.  We have been exploring the synthesis of all azaindole isomers, and related compounds, bearing varied substitution patterns useful for drug discovery.  These studies have led to the discovery of new routes to these compounds and the production of compounds bearing useful functional groups in unusual substitution patterns.

From these compounds, we have prepared diverse lead-like libraries for high throughput screening studies.  The design of these libraries provides libraries that are diverse, yet with sufficient similarity built in to allow immediate confirmation of any hits.  The poster will present the design of these libraries as well as challenges encountered during synthesis and purification.

5 Abstract:  High-throughput screening of a library of compounds has led to the identification of a new structural class of human methionine aminopeptidases inhibitors.  They inhibited the processing of 14-3-3g in cells and blocked proliferation of both endothelial cells and transformed cancer cells lines.  The picture shows the crystal structure of the complex of one inhibitor (yellow) with the type 1 human methionine aminopeptidase (blue CoII, red H2O).

6 Abstract:  With >1 million deaths annually, mostly among children insub-Saharan Africa, malaria poses one of the most critical challengesin medicine today. Although introduction of the artemisininclass of antimalarial drugs has offered a temporary solutionto the problem of drug resistance, new antimalarial drugs areneeded to ensure effective control of the disease in the future.Herein, we have investigated members of the methionine aminopeptidasefamily as potential antimalarial targets. The Plasmodium falciparummethionine aminopeptidase 1b (PfMetAP1b), one of four MetAPproteins encoded in the P. falciparum genome, was cloned, overexpressed,purified, and used to screen a 175,000-compound library forinhibitors. A family of structurally related inhibitors containinga 2-(2-pyridinyl)-pyrimidine core was identified. Structure/activitystudies led to the identification of a potent PfMetAP1b inhibitor,XC11, with an IC50 of 112 nM. XC11 was highly selective forPfMetAP1b and did not exhibit significant cytotoxicity againstprimary human fibroblasts. Most importantly, XC11 inhibitedthe proliferation of P. falciparum strains 3D7 [chloroquine(CQ)-sensitive] and Dd2 (multidrug-resistant) in vitro and isactive in mouse malaria models for both CQ-sensitive and CQ-resistantstrains. These results suggest that PfMetAP1b is a promisingtarget and XC11 is an important lead compound for the developmentof novel antimalarial drugs.

Abstract 7:  CPSA 2005 demonstrated that industry is investing a great deal of resources to achieve LC-MS run times less than 2 minutes. Methods including FAIMS-ESI-MS, chip-based nanoelectrospray and 5x flow rates were presented. The LC-MS method described herein has a 1.5 minute run time and is capable of running an average of 550 compounds per 24-hour period per instrument. The method demonstrates the resolution, precision and robustness required for successful semi-quantitative analysis of diverse chemical compounds dissolved in dimethyl sulfoxide. Another question that arose at CPSA 2005 was how does one validate a method designed for diverse chemical analysis. An abbreviated validation study is also defined for liquid chromatographic methods that are designed to analyze diverse collections of chemical compounds used in the pharmaceutical industry including drug-like compounds, fragments, scaffolds and intermediates. The criteria for assuring diversity of the chemical compounds to be used as controls in the validation studies include a diverse mass range, a large molar absorptivity coefficient and structural diversity. Three properties are monitored in the validation study and include resolution, precision and robustness. A daily control program monitors instrument performance. The parameters for this control program measure the efficacy of the system via monitoring column performance (resolution), UV lamp efficacy (response) and mass reproducibility (precision). A 2-sigma control model is defined and the above parameters are monitored via Levy-Jennings charts.