See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/235084800 Prediction of Health and Environment Hazards of Chemicals: A Hierarchial Approach Using QMSA and QSAR Article · September 2000 CITATIONS READS 0 136 1 author: Subhash C Basak University of Minnesota Duluth 546 PUBLICATIONS 10,342 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: OpenTox View project Mol2Net Conference View project All content following this page was uploaded by Subhash C Basak on 27 May 2014. The user has requested enhancement of the downloaded file. REPORT DOCUMENTATION PAGE AFRL-SR-BL-TR-00- Public reporting burden for this collection of information is estimated to average 1 hour per respon; data sources, gathering and maintaining the data needed, and completing and reviewing the collection of inform; aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquart 215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Buc 0503. 1. AGENCY USE ONLY (Leave blank) 2. REPORT DATE 3. REPORT TYPFWTOTOTTTsrcuvrxtED" September 28, 2000 Final - October 1, 1997 - September 30, 2000 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Prediction of Health and Environment Hazards of Chemicals: A Hierarchial Approach F49620-98-1-0015 Using QMSA and QSAR 6. AUTHOR(S) Dr. Suhhash C. Basak Natural Resources Research Institute 7. PERFORMING ORGANIZATION NAME{S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION University of Minnesota REPORT NUMBER 5013 Miller Trunk Highway Duluth, MN 55811 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10 SPONSORING/MONITORING AFOSR/NL AGENCY REPORT NUMBER 801 North Randolph Street, Room 732 Arlington, VA 22203-1977 11. SUPPLEMENTARY NOTES 12a. DISTRIBUTION AVAILABILITY STATEMENT 12b. DISTRIBUTION CODE APPROVED FOR PUBLIC RELEASE: DISTRIBUTION UNLIMITED 13. ABSTRACT (Maximum 200 words) During the first year of the project, the majority of effort was spent in the development of novel hierarchial QSAR methods, QMSA techniques and the applications of these methods in the prediction of toxicological, physiochemical and biomedicinal properties of different sets of chemicals. During the second year of the project, our effort was directed towards the development of novel optimal molecular descriptors, the development and use ofnew topological indices, the study of the intercorrelation of a large number of molecular descriptors, and the use of calculated molecular descriptors in the prediction of toxicological and toxicologically-relevant properties. The third year of the project focused on the further expansion of our theoretical molecular descriptor set through the further development of new topological indcies and the acquisition of several other well-known software packages for the calculations of molecualr descriptors, viz., CODESSA v2.0 and MolconnZ- V3.50. 14. SUBJECT TERMS 15. NUMBER OF PAGES Chemicals, QMSA, QSAR 177 16. PRICE CODE 17. SECURITY CLASSIFICATION 18. SECURITY CLASSIFICATION 19. SECURITY CLASSIFICATION 20. LIMITATION OF ABSTRACT OF REPORT OF THIS PAGE OF ABSTRACT Unclas Unclas Unclas Standard Form 298 (Rev. 2-89) (EG) Prescribed by ANSI Std. 239.18 Designed using Perform Pro, WHS/DIOR, Oct 94 Final Report of the Air Force Project Covering research period 8/1/97 to 9/30/00 Agency No: DOD/F49620-98-1-0015 UofM No: 1613-189-6158 NRRI Technical Report No: NRRI/TR-2000/44 Prediction of Health and Environmental Hazards of Chemicals: A Hierarchical Approach Using QMSA and QSAR September 28, 2000 Submitted by: Subhash C. Basak, Ph.D. Principal Investigator Natural Resources Research Institute University of Minnesota, Duluth 5013 Miller Trunk Highway Duluth, MN 55811 Tel: (218)720-4230 Fax: (218)720-4328 Email: [email protected] The University of Minnesota is an equal opportunity educator and employer. DTIC QUALITY IErH?B©IEH5 4 20001106 100 Table of Contents OBJECTIVES 3 STATUS OF EFFORTS 4 ACCOMPLISHMENTS/NEW FINDINGS 4 TASKI: DEVELOPMENT OF DATABASES 4 TASK 2: DEVELOPMENT OF A COMPREHENSIVE COMPUTER PROGRAM FOR CALCULATING TOPOLOGICAL MOLECULAR DESCRIPTORS 4 TASK 3: INTEGRATION OF GRAPH THEORY AND QUANTUM CHEMISTRY FOR QSAR 5 TASK 6: CHARACTERIZATION OF STRUCTURE USING THEORETICAL STRUCTURAL DESCRIPTORS..... 5 TASK 7: DEVELOPMENT OF HIERARCHICAL QMSA MODELS 5 TASK 8: DEVELOPMENT OF HIERARCHICAL APPROACH TO QSAR 6 PERSONNEL SUPPORTED 6 PUBLICATIONS 7 INTERACTIONS/TRANSITIONS 9 TRANSITIONS 9 MEETINGS/ SEMINARS/ INVITED PRESENTATIONS 10 HONORS AND AWARDS 15 NEW DISCOVERIES/ INVENTIONS, PATENT DISCLOSURES 15 APPENDICES 16 Objectives During the past few years we have been involved in the development of new computational methods for quantifying similarity/dissimilarity of chemicals and applications of quantitative molecular similarity analysis (QMSA) techniques in analog selection and property estimation for use in the hazard assessment of chemicals. We have also explored the mathematical nature of the molecular similarity ^ space in order to better understand the basis of analog selection by QMSA methods. The parameter spaces used for QMSA and analog selection were constructed from nonempirical parameters derived from computational chemical graph theory. Occasionally, graph invariants were supplemented with geometrical parameters and quantum chemical indices to study the relative effectiveness of graph invariants vis-ä-vis geometrical and quantum chemical parameters in analog selection and property estimation. We carried out comparative studies of nonempirical descriptor spaces and physicochemical property spaces in selecting analogs. Molecular similarity methods were applied in predicting modes of toxic action (MOA) of chemicals. Our similarity/dissimilarity methods have also found successful applications in trie discovery of new drug leads by US drug companies. In this project, we will have four primary goals: 1) development of a hierarchical approach to molecular similarity, 2) formulation of quantitative structure-activity relationship (QSAR) models for predictive toxicology using a hierarchical approach, 3) applications of hierarchical QSAR and QMSA approaches in computational toxicology related to human health and ecological hazard assessment, and 4) the application of hierarchical QMSA and QSAR approaches in estimating potential toxicity of deicing agents. The first goal of the project is the use of parameters of gradually increasing complexity, viz., topological, topochemical, geometrical, and quantum chemical indices, in the quantification of molecular similarity/dissimilarity of chemicals. We will take a two-tier approach in this area. First, similarity methods will be used in ordering sets of molecules and in selecting structural analogs of toxic chemicals which pose human health and ecological hazards. Secondly, we will use the properties of selected analogs in estimating toxicologically important properties for chemicals. Although different classes of parameters have been used in the characterization of molecular similarity, no systematic study has been carried out in the use of all four classes of parameters, mentioned above, in analog selection and property estimation. We will apply a hierarchical approach to the use of these four types of theoretical molecular descriptors in the quantification of molecular similarity/dissimilarity. The second goal consists of the development of hierarchical QSAR models for predicting the toxic potential of chemicals using topological and quantum chemical indices. Initially, we will use parameters calculated by semi-empirical methods such as MOPAC and AMPAC. Parameters calculated by ab initio quantum chemical methods will be used in limited cases of QSAR model development, if they are considered necessary. The third goal of the project will be the prediction of human health hazard and ecotoxicological effects of chemicals using QSAR and QMSA methods developed in the project. Attempts will be made to estimate endpoints, such as, carcinogenicity, mutagenicity, xenoestrogenicity, acute toxicity, transport of chemicals through the blood-brain barrier, biodegradation, and bioconcentration factor. The fourth goal will involve the utilization of QMSA and QSAR methods developed as part of this project in predicting the potential toxicity of deicing agents. Prediction of Health and Environmental Hazards of Chemical: A Hierarchical Approach Using QMSA and QSAR- Subhash C. Basak Status of Efforts During the first year of the project the majority of effort was spent in the development of novel hierarchical QSAR methods, QMSA techniques and the applications of these methods in the prediction of toxicological, physicochemical and biomedicinal properties of different sets of chemicals. Our dissimilarity methods were used to group JP-8 constituents into a small number of clusters that can be used in selecting surrogate mixtures for JP-8 in the Air Force's toxicological studies. The clustering was done using algorithmically derived molecular descriptors calculated by our computer program POLLY. Such parameters can be calculated for any molecular structure, real or hypothetical. This makes the clustering methods independent of any experimentally determined property of the JP-8 constituents. During the second year of the project, our effort was directed towards the development of novel optimal molecular descriptors, the development and use of new topological indices, the study of the intercorrelation