Structure-activity analysis

C. Hansch, A. Leo, Exploring QSAR American Chemical Society, Washington (1995). L. B. Kier, L. H. Hall, Molecular Connectivity in Structure-Activity Analysis Research Studies Press, Chichester (1986). 

M Randic. On characterization of molecular branching. J Am Chem Soc 97 6609-6615, 1975. LB Kier, LH Hall. Molecular Connectivity in Structure-Activity Analysis. Chichester, England Research Studies Press, 1986. 

Maxwell DM, Brecht KM. 1992. Quantitative structure-activity analysis of acetylcholinesterase inhibition by oxono and thiono analougues of organophosphorus compounds. Chem Res Toxicol 5 66-71. 

Kier LB, Hail LH. Molecular connectivity in structure-activity analysis. New York John Wiley Sons, Inc., 1986. 

A. Verloop, The STERIMOL Approach to Drug Design. Marcel Dekker, New York, 1987. L.B. Kier and L.H. Hall, Molecular Connectivity in Structure-Activity Analysis. Wiley, New York, 1986. 

Zhang Y, Ernst CA, Rollins BJ. MCP-1 structure/activity analysis. Methods 1996 10(1) 93—103. 

Martin, Y. C., A practitioner s perspective of the role of quantitative structure-activity analysis in medicinal chemistry, J. Med. Chem. 1981, 24, 229-237. 

Besides the applications of the electrophilicity index mentioned in the review article [40], following recent applications and developments have been observed, including relationship between basicity and nucleophilicity [64], 3D-quantitative structure activity analysis [65], Quantitative Structure-Toxicity Relationship (QSTR) [66], redox potential [67,68], Woodward-Hoffmann rules [69], Michael-type reactions [70], Sn2 reactions [71], multiphilic descriptions [72], etc. Molecular systems include silylenes [73], heterocyclohexanones [74], pyrido-di-indoles [65], bipyridine [75], aromatic and heterocyclic sulfonamides [76], substituted nitrenes and phosphi-nidenes [77], first-row transition metal ions [67], triruthenium ring core structures [78], benzhydryl derivatives [79], multivalent superatoms [80], nitrobenzodifuroxan [70], dialkylpyridinium ions [81], dioxins [82], arsenosugars and thioarsenicals [83], dynamic properties of clusters and nanostructures [84], porphyrin compounds [85-87], and so on. 

Mr. Don Clay, Director of the Office of Toxic Substances, discussed the premanufacture review procedures and experience with PMNs to date at a meeting of the Organization for Economic Cooperation on Development (OECD) Chemicals Forum in December, (10). He noted that EPA s chemistry, toxicology, and exposure assessment teams normally complete their preliminary evaluation within a week of receipt of a PMN, and, that preliminary assessment eliminates about 50 percent of the substances as chemicals of low concern. They then proceed to structure activity analysis and reasonable worst case assumptions to assess unreasonable risk or the need for more data. 

De Benedetti, P.G., Cocchi, M., Menziani, M.C. and Fanelli, F. (1993) Theoretical quantitative structure-activity analysis and pharmacophore modelling of selective non congeneric ala-adrenergic antagonists. Journal of Molecular Structure (Theochem), 280, 283-290. 

Kundu B, Richardson SD, Granville CA, Shaughnessy DT, Hanley NM, Swartz PD, Richard AM, DeMarini DM (2004) Comparative mutagenicity of halomethanes and halonitromethanes in Salmonella TAIOO structure-activity analysis and mutation spectra. Mutat Res 554(l-2) 335-350... 

None of these had pronounced herbicidal activity but rather PGR activity. Compound % for example, has been shown to be an auxin transport inhibitor, a property probably shared by the other members of this class also. A structure activity analysis for this group of compounds has been reported by Katekar ( ) ... 

Seewald, I, Michel, H. Klepel, M. Held, P. Ohmann, E. Barth, A. Metzger, U. in "Quantitative Structure-Activity Analysis Akademie Verlag, Berlin, 1978, 77. 

The measure of chemical diversity of a set of compounds clearly depends on the descriptor variables chosen to characterize their chemical structures. Similarly, the utility of a structure-activity analysis will depend on how well the descriptor variables capture the important chemical features. 

For example, we address the following questions. Does diversity generated by one method and descriptor set correspond to diversity according to another How do various designs compare with random selections In structure-activity analysis, does one method outperform another in the identification of active compounds ... 

Figure 1. The structures of the uir-inducing phenolic compounds employed in our structure-activity analysis (41).

A.F. Spatola, Peptide backbone modifications A structure-activity analysis of peptides containing amide bond surrogates, conformational constraints, and related backbone replacements, in B. Weinstein(Ed.), Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, Marcel Dekker, New York, 1983, pp. 267-357. 

In addition to the effects noted above, the ergot alkaloids produce a variety of other central nervous system and peripheral effects. Detailed structure-activity analysis and appropriate semisynthetic modifications have yielded a large number of agents of interest. 

After synthesis and biological investigation of the test compounds the medicinal chemist has two types of information in hand, i.e. one refering to the chemical structure and the respective physico-chemical properties and an other one which concerns the biological properties of the compounds. The way in which the latter properties depend on the former ones can be determined by structure-activity-analysis which yields structure-activity-relationships (detailed accounts can be found... 

Considering the last two paragraphs one encounters an other problem of systematic drug design In order to select appropriate test compounds one needs to know the relevant parameters. These in turn can only be found through structure-activity-analysis based on the selected compounds. In other words, one needs to know the results which are obtained from the test series before this series can be designed properly. How can this problem be solved As in other similar cases (e.g. the calculation of orbital energies in quantum mechanics) an iterative procedure can be applied. Such a procedure is visualized in Scheme 1. 

What requirements must parameters fulfil in order to be suitable in the search for new drugs The type of parameter which is principally suitable depends on the respective problem, i.e. whether we are concerned with series design or with derivation of structure-activity-relationships. In the former case only parameters which can be calculated directly from the chemical structure can be used whereas in the latter case one can also (and preferably) apply measured parameters. Thus, measured log P values as well as calculated ones ( ) are suitable in structure-activity-analysis, whereas for series design lipophilicity can only be represented by the calculated values. 

By using measured values in structure-activity-analysis more reliable structure-activity-relationships may be obtained, but higher experimental expense is normally required. When is this expense justified This is only the case if the deviation between the calculated and the measured values of the physico-chemical property exceeds all the other errors which enter the respective structure-activity-relationships or if measuring requires less effort than calculation. 

In conclusion, for series design and largely also for evaluation of test series by structure-activity-analysis, the parameters which are used to describe physicochemical properties should meet the following condition ... 

Structure-Activity Analysis In Vitro Tests Animal Bioassays Epidemiology... 

Brooks TA, Kennedy DR, Gruol DJ, Ojima I, Baer MR, Bernacki RJ (2004) Structure-activity analysis of taxane-based broad-spectrum multidrug resistance modulators. Anticancer Res 24, 409-415. 

Croisy, and P.C. Jacquignon. A quantitative structure-activity analysis of the mutagenic and carcinogenic... 

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