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| Professor Kenneth M. Merz, Jr., Chief Scientific Officer of QuantumBio |
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Kenneth M. Merz, Jr. is currently a Professor of Chemistry at the University of Florida and a Member of the Quantum Theory Project. Prior to this he was an Assistant, Associate and Professor of Chemistry at the Pennsylvania State University from 1989-1995. He also has worked in industry (1998-2001) first as the Senior Director of the Center for Informatics and Drug Discovery (CIDD) at Pharmacopeia, Inc. and then as the Senior Director of the ADMET Research and Development Group in the Accelrys software division of Pharmacopeia. He is currently the Chief Scientific Officer of QuantumBio.
Dr. Merz carried out postdoctoral training at The University of California, San Francisco (1987-1989, with Peter Kollman) and at Cornell University (1986-1987, with Roald Hoffmann). He received his Ph.D. in Organic Chemistry at The University of Texas at Austin in 1985 (with M. J. S. Dewar) and his B.S. from Washington College, Chestertown, Maryland in 1981. He has received a number of honors including election as a fellow of the American Association for the Advancement of Science (1999) and a John Simon Guggenheim Fellowship (1996).
A recognized leader in the field of computational chemistry, he has published over 150 articles in peer-reviewed journals and given more than 150 presentations worldwide since he joined the Penn State Chemistry Department in 1989. He has received numerous academic honors including being elected a Fellow of the American Association for the Advancement of Science and a Guggenheim Fellowship. In his industrial roles, Dr. Merz has had responsibility for assessing market opportunities, designing product offerings and overseeing the creation and development of products. To do so, he has worked closely both with bench chemists and biologists at Pharmacopeia who were in-house software users, as well as purchasers and users of modeling tools from outside customers.
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Quantum Mechanics for Drug Discovery (Web Conference Presentation)
Quantum mechanics (QM), although not new to the field of molecular interactions, has till now been used only to study small systems because of the computational cost associated with it. Recently, a "linear-scaling revolution" is occurring in quantum mechanics. This development is allowing for the first time the routine examination of large molecular assembles (e.g., proteins and DNA in water) using electronic structure methods. One of these approaches is the divide and conquer method, which is now implemented in the DivCon Discovery Suite by QuantumBio Inc.
We have implemented this divide & conquer linear-scaling semi-empirical QM methodology into several applications. We will cover five of them, and they are:
1) QM based scoring function - The current generation of scoring functions can be grouped into three categories: empirical scoring functions, knowledge-based potentials and force field methods. While all classes of scoring functions have shown success in selected cases and environments, there are however no reports of those 3 classes of scoring functions working effectively in all general cases. Furthermore, metal-containing systems pose a challenge for these scoring functions due to the nature of the interactions between a small molecule and a metal ion in the active site. Various metal-ligand interactions are difficult to model and predict with simpler scoring functions, but are much better expressed by QM.
2) The charge distribution of biological molecules in solution as described by quantum mechanics will be discussed. In particular, the role polarization and charge transfer plays in affecting the charge distribution of proteins will be discussed.
3) The energetic consequences of charge transfer and polarization on biomolecular solvation will be discussed.
4) The computation of solvation free energies using a combined divide and conquer/Poisson-Boltzmann approach will be discussed.
5) NMR Chemical Shift Perturbation prediction based on divide and conquer QM will be discussed. The current NMR prediction tools lack the accuracy to predict the interaction on the protein and to study weakly bound ligands.
The application of the divide and conquer linear-scaling semi-empirical quantum mechanical method to biology is only just beginning, but the future is very bright, and it is our opinion that quantum mechanics will have a profound influence on our understanding of biological systems and accelerating drug discovery in the coming years.
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The Role of Quantum Mechanics in Structure-Based Drug Design
Kenneth M. Merz Jr, Department of Chemistry, Quantum Theory Project, 2328 New Physics Building, P.O. Box 118435, University of Florida, Gainesville, Florida 32611-8435, USA and QuantumBio, 200 Innovation Park, Suite 261, State College, PA 16803, USA
Semiempirical quantum chemical (QM) methods have had tremendous impact on our understanding of chemical and biological systems. In this presentation we will focus on the application of semiempirical QM methods to solve relevant problems in structure-based drug design (SBDD). For example, we will describe recent application of these methods to the scoring of protein-ligand poses, NMR spectroscopy, X-ray spectroscopy, pairwise energy decomposition of protein-ligand complexes and in QM/QSAR applications. Finally, we will summarize our vision of the future application of quantum chemistry to SBDD.
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