From chemistry-request@ccl.net Fri Mar 27 12:11:12 1992 Date: Fri, 27 Mar 1992 10:19 CST From: Andy Holder Subject: Semiempirical references. To: CHEMISTRY@ccl.net Status: R Fellow Netters, Below is the compendium that I collected on the "success stories" on the application of semiempirical methods My focus was on commercial or "real world" applications, and I received quite a few entries that didn't fit into this categorization. I am surprised at the paucity of such data, but as I said in my original posting, a great deal of this is proprietary (I hope!). I would like to continue to expand this database so please pass along any further items you have. Thanks to all those who responded and to Clarke Earley here at UMKC for helping with the summaries. Enjoy... Andy =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= DR. ANDREW HOLDER Assistant Professor of Computational/Organic Chemistry Department of Chemistry || BITNET Addr: AHOLDER@UMKCVAX1 University of Missouri - Kansas City || Internet Addr: aholder@vax1.umkc.edu Spencer Chemistry, Room 502 || Phone Number: (816) 235-2293 Kansas City, Missouri 64110 || FAX Number: (816) 235-1717 =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-= 1. Boyd, D. B.; Eigenbrot, C.; Indelicato, J. M.; Miller, M. J.; Pasini, C. E.; Woulfe, S. R. J. Med. Chem. 1987, 30, 528. In the search for new beta-lactam antibiotics (penicillins fall in this class of compounds), it was found that sulfur-based drugs (thiamazins) displayed no activity while the traditional oxygen-based drugs (oxamazins) were useful. The explanation of this surprising behavior was partially explained by semiempirical calculations, which indicated that the structure of the inactive drugs results in a poor fit with the "active site". These calculations (which utilized the AM1, MNDO, and MINDO/3 methods) were also able to show that several other factors were probably not important, which lowers the likelihood that potentially useful drugs will be eliminated without consideration. 2. Boyd, D. B. in Successes of Computer-Assisted Molecular Design; 1990; pp 362. Myclobutanil is a broad spectrum, agrochemical fungicide. After narrowing the possible types of compounds that appeared useful by field testing, differences between the activity of these molecules were correlated with a number of molecular properties, including an analysis of molecular charges calculated using the semiempirical MNDO method. The eventual development of myclobutanil was credited as a direct result of this analysis. 3. Earley, C. W. Inorg. Chem. 1992, in press. It is estimated that over 400,000 tons of zeolites are used annually, primarily in petroleum refining processes. Since these are solid state materials, both experimental and theoretical investigations are quite difficult. However, it has been shown that the results of quantum mechanical calculations on isolated molecules can be successfully applied to enhance understanding some of the properties of these solid-state materials. In this case, AM1 calculations on molecules containing as few as two or three silicon centers can be used to explain one of the basic structural features of these molecules, and semiempirical calculations on larger molecules have been used to determine the most acidic sites. 4. Holder, A. J.; Upadrashta, S. J. Pharm. Sci. 1992, in press. The antipsoriatic drug anthralin has been in use for over 60 years. This AM1 study explains some of the properties that make the drug active and suggests further directions for research. 5. Kador, P. F.; Sharpless, N. E. Molec. Pharm. 1983, 24, 521. Clinical trials of an aldose reductase inhibitor suggests that these types of compounds can prevent certain eye problems (cataract formation and corneal re-epithelialization) in diabetic patients. Clinical studies indicate that no "universally potent" inhibitor exists, emphasizing the need to find new drugs of this type. Comparison of the activities of several of these drugs with results of quantum mechanical calculations (energies of lowest unoccupied molecular orbitals and atomic charges) showed strong correlations, which aided in prediction of the minimal requirements for an active drug. 6. Kehl, H.; Holder, A. J. J. Pharm. Sci. 1991, 80, 139. GABA (gamma-aminobutyric acid) is a mediator of the central nervous system and has been implicated as a contributor in chemically-induced depression. A theoretical study using the AM1 method on GABA and two derivatives of this compound was able to show that one of these derivatives is more closely related to the parent system than the second. This result is in agreement with the actual experimental results. 7. Ripka, W. C.; Sipio, W. J.; Blaney, J. M. Lect. Heterocyc. Chem. 1987, IX, S95. The Phospholiphase A2 enzyme is thought to be involved in the breakdown of phospholipids, important components in living systems. This study was undertaken to show that theoretical methods can be successfully applied to drug design. Analysis of the geometries of a number of proteins suggested one key structural component. Quantum mechanical calculations not only supported these findings, but were also able to offer a simple explanation for this phenomenon. 8. Szarek, W. A.; Smith, V. H.; Woods, R. J. J. Am. Chem. Soc. 1990, 112, 4732. Quantum mechanical calculations on a number of simple sugars provided an explanation of the relative sweetness of these compounds. Analysis of the structural features observed in the calculated geometries of these compounds suggests that a previously neglected feature of these molecules may be impor- tant in determining "sweetness". 9. Wasielewski, M. R.; Johnson, D. G.; Bradford, E. G.; Kispert, L. D. J. Chem. Phys. 1989, 91, 6691. Caroteniods are light-gathering agents in the pigments of eyes. In order to understand the efficiency of these compounds in transferring light energy, a theoretical study using the AM1 method was performed. The explanation for the high efficiency of this process obtained from these calculations was in agreement with the results of experimental studies. 10. Culberson, J. C.; Walters, D. E. 199th National Meeting of the American Chemical Society, 1990, 214. Muller, G. W.; Walters, D. E.; DuBois, G. E. J. Med. Chem. 1 992, 35, 740. Hallinan, E. A.; Walters, D. E.; DuBois, G. E.; Mazur, R. H.; Muller, G. W. J. Agric. Food. Chem. 1991, 39, 1836. These three references describe cxomputational work on defining the sweet receptor and investigating compounds to interact with it more advantageously.