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| Gilles Klopman, Multicase |
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A native of Belgium, Dr. Gilles Klopman came to Case Western Reserve University as an Associate Professor of Chemistry in 1967 and was promoted to Professor in 1969. He earned both his undergraduate and graduate degrees from the University of Brussels, working under the direction of Professors Prigo-gine and Martin. He received his Doctorate with highest honors in 1960 for his thesis on the Synthesis and Study of the Physical Chemical Properties of Non Alternant Aromatic Hydrocarbons. After a year in the Military, where he worked on the polarographic determination of trace elements (lead and copper) in blood and tissues, he joined the Organic Group at the Cyanamid European Research Institute in Geneva Switzer-land. In Geneva, his interest in mechanistic and applied theoretical chemistry grew from his collaboration with Profs. R.F. Hudson and C.K. Jorgensen. It is in the early 60's that his pioneering work on the development of semi-empiri-cal methods of calculating the properties of nonconjugated molecules attracted attention to his work. This prompted an invitation to spend a sabbatical year with Professor M.J.S. Dewar at the University of Texas in Austin, where he developed, in 1965, what was to become known as the MINDO method.
Dr. Klopman has authored or coauthored three books and more than three hundred and twenty research papers. His research interests range from experimental deter-mination of reactivity indices and substituent constants to the development of reactivity theories. His descriptions of Perturbation theory and of the concept of Charge and Orbital controlled Reactions are now widely used to explain the ambident selectivity of nucleophiles and links the Linear Free Energy type correlations (Hammett, HSAB etc..) to more fundamental chemical concepts. His interest in quantum mechan-ics and computers has led him to design and program one of the first semi-empirical SCF methods for the calculation of the properties of saturated molecules.
Dr. Klopman's interests have gradually moved toward problems of artificial intelligence and its general use to extract useful information from large databases. As part of this effort, his group has developed, in the last 20 years, a set of computer packages, acronymed CASE (Computer Automated Structure Evaluation) and MultiCASE to represent and manipulate chemical databases, especially those related to biological activity. These programs use a unique way to examine large databases of diverse chemicals and identify automatically the structural entities that are responsible for the observed biological activity. This is supplemented by more traditional QSAR to extract quantitative information. This information is then used to assess the activity of molecules that have not yet been tested, or even synthesized. The program has been used to assess both pharmacological and toxic activities. Hundreds of databases have been developed and studied with the help of his programs. The majority of these databases deal with the safety of chemicals and pharmaceuticals both to human life and to the environment. Databases for carcinogenicity, mutation, teratogenicity, biodegradation, fish toxicity, endocrine disruption and so on have all been evaluated successfully by MultiCASE. As a result, the program is now seen as a valid replacement of animal testing and, with the support of the Humane Society, Dr. Klopman has been disseminating the notion that there is an alternative to assessing the potential harmful effect of chemicals without using animals.
Dr. Klopman has been invited to lecture at many national and international conferences and present seminars in many American, European and Japanese universities. He was awarded the Stas Spring medal from the Belgian Academy of Sciences and, in 1971, was awarded a Kahlbaum lectureship at the University of Basel, Switz-erland. In 1974, he was invited to spend a semester as a visiting Professor at the "Centre de Mecanique Ondulatoire Appliquee" in Paris, France where he worked with Professor R. Daudel. In 1982, he was a visiting Professor at the University of Geneva, Switzerland where he gave a series of lectures on "Chemical Reactivity". In 1993, he received the Morley medal and in 2005, the Patterson-Crane award from the American Chemical Society.
His interest in technology transfer has also led to a major involvement in Business. He helped found 3 companies, BIOFOR, a pharmaceutical company and two software companies, Discovery Software and MULTICASE Inc. He currently serves as the President and CEO of the latter Company whose business consists in licensing his latest software and toxicological databases. In January 1998, MultiCASE Inc. signed a CRADA agreement with the Federal Drug Administration CDER office to develop Carcinogenicity and Teratogenicity databases for use by the FDA and available to Industry from MULTICASE Inc. Since then, his MC4PC has been adopted not only by the USFDA but also by the equivalent Canadian, Japanese and Danish Agencies in their regulatory functions. MULTICASE has now become the leading expert system in Computational Toxicology with many industrial users in the US as well as Belgium, Canada, Denmark, France, Germany, Netherlands, Sweden, Switzerland and Japan.
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MULTICASE Software for Toxicity Predictions
Gilles Klopman, Multicase
The workshop will illustrate:
1. The use of MC4PS to evaluate the potential safety of chemicals
2. Demonstration of the creation of a new model to be used to predict the outcome of mouse lymphoma assay of new chemicals.
3. Demonstration of the use of ”In Silico technique” to identify new safe anti-HIV agents.
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Machine Intelligence in the Design of New Biologically Active Chemicals
Gilles Klopman, Multicase
The design of new biologically active chemicals, whether pharmaceuticals or agricultural requires a good understanding of their potential beneficial activity, their ability to reach and act upon their intended target, and lack of detrimental or toxic effects.
Enormous resources go into the development of new chemicals and it is extremely desirable to find ways to assess these properties at the earliest possible stage so as to minimize the number of expensive failures. In this lecture, several such techniques, developed in the lecturer’s laboratory will be described and demonstrated. These techniques are now in use at various sites of the US FDA for the purpose of assessing the safety of new pharmaceuticals and other chemicals.
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