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| About James P. Snyder (Emory University) |
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Jim Snyder originally trained as a synthetic organic chemist at Cornell University in the area of polycyclic heterocycles. He initiated independent research by applying physical organic principles to rate variations in a series of asymmetric thermal pericyclic reactions at Yeshiva University (NYC) and University of Copenhagen in the 1970’s. PhD students were encouraged to blend both experiment and computer modeling in their research studies.
In 1981, he switched horses and joined Merck Sharp and Dohme in Rahway, N.J. to integrate medicinal and computational chemistries. The industrial environment provided exposure to principles of enzyme inhibition, receptor binding, metabolism, peptide/protein conformation and biochemical mechanism. Three years later he assumed leadership of the computational unit - Drug Design - at Searle/Monsanto. The group attempted to influence the discovery of candidate drugs in a variety of therapeutic areas. To this end, their primary goal was the promotion of productive three-way partnerships among synthetic chemists, biologists and computational scientists. The process of fully integrating the three disciplines is still evolving in industry and academia today (cf. J. P. Snyder, Computer-assisted Drug Design: Condition in the 1980’s. Med.Res.Rev. 1991, 11, 641-662). In 1991, his responsibilities were broadened to include management of the Cellular Pharmacology Laboratory responsible for performing automated radioligand binding assays (i.e. very early high-throughput screening – HTS).
In early 1993, he accepted a position at IRBM (Institute for Research in Molecular Biology), a chariot ride south of Rome, Italy, to establish a department of chemistry. Within 1.5 years the department grew to 13 synthetic chemists, 2 computational chemists and an expert in pharmacokinetics. They sought inhibitors of the hepatitis B virus RNA polymerase and the hepatitis C serine protease. In 1995, he returned to the U.S. as a teacher and Director of Biostructural Research at Emory University; Atlanta, Georgia.
Within the context of drug candidate design, the interaction between ligand and macromolecular acceptor in an aqueous milieu is fundamental. Numerous collaborations have been established to exploit and explore this concept and to develop therapeutic agents for neuroprotection and stroke (Dingledine, Traynelis, Liotta), paramyxoviruses (Plemper, Sun), Alzheimer’s amyloid structure (Lynn), inflammation and immune system disorder (Zimmer) and cancer (super-active Taxol analogs and bridged epothinlones (Kingston, Bane), metastasis & CXCR4 (Liotta, Shim, Natchus), head-&-neck and lung (Fu, Liotta), breast and cell targeting (Shoji, Liotta) and CD7 kinase action (Barrett)). Some of these efforts have helped to spawn several small drug-seeking start-up companies: Metastatix, Curry Pharmaceuticals and NeurOp Inc.
On the purely chemical research side, his group is engaged in several studies concerning molecular conformation in solution as it pertains to bioactive conformation and energy of the same molecules bound to proteins; protein conformational change as the basis for biological action; and redox fluctuation in organometallic reactions.
His work has lead him from the university to industry and back again. During both periods, he has tried to serve the community as a research-oriented teacher by means of workshops and short courses in the U.S. and Europe. At Emory, this has meant development of a new undergraduate course “Chemistry, Biology and Molecular-Modeling” that touches many aspects of life (disease, death, vanity, color, the senses …) and asks the students to see it all through the medium of 3D molecular structure (cf. http://webdrive.service.emory.edu/groups/college/ctrscied/www/chem330/index.htm)
Jim Snyder has 200 published and peer-reviewed papers and over 30 patents.
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What Energy Price Does a Drug Pay To Bind To a Protein Target?
James P. Snyder*, Ana Alcaraz, Seth Childers, Yong Jiang, Scott Johnson, Andy Prussia, Pahk Thepchatri, Suwipa Saen-oon, Jennifer Sorrells
If a molecule in equilibrium with one or more conformers in solution is characterized by a relative DG > 3 kcal/mol, its population is < 99.4% at 298 K. Chemists use this rule-of-thumb to rationalize yields and relative rates of reactions, while medicinal chemists apply it to the ligand-protein binding process. If the conformational strain of a drug or ligand conformation is much higher than 3 kcal/mol, it is believed by many that such a ligand has a low probability of binding to its macromolecular target. Over the past 10 years, several computational studies have attempted to verify the 3-kcal rule. With conflicting interpretations placing the accessible energy window somewhere between 3 and 40 kcal/mol, agreement has yet to be reached. The most comprehensive and recent study on 150 proteins complexed with drug-like ligands by Perola and Charifson (J. Med. Chem. 2004, 47, 2499-2510) suggests that global strain energies of 10 kcal/mol are common (i.e. at least 10% of ligands), while 25 kcal/mol ligand strain energy can be tolerated within protein-ligand complexes. In the present study, we examine this concept by evaluating structures and energies of both bound and “free” ligands; namely X-ray structures for the former and conformationally generated global minima for the latter. By combining molecular mechanics calculations, the fits of small molecules to X-ray crystallographic densities and NMR analysis of the conformations of ligands in solution, we conclude that it is likely that drug conformational strain energy rarely exceeds 3-5 kcal/mol in the protein binding event.
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