Abstract
QSAR (quantitative structure–activity relationship) is a method for predicting the physical and biological properties of small molecules; it is today in large use in companies and public services. However, as any scientific method, it is nowadays challenged by more and more requests, especially considering its possible role in assessing the safety of new chemicals. Posing the question whether QSAR is a way not only to exploit available knowledge but also to build new knowledge, we shortly review QSAR history, thus searching for a QSAR epistemology. We consider the three pillars on which QSAR stands: biological data, chemical knowledge, and modeling algorithms. Most of the time we assume that biological data is a true picture of the world (as they result from good experimental practice), that chemical knowledge is scientifically true; so if a QSAR is not working, blame modeling. This opens the way to look at the role of modeling in developing scientific theories, and in producing knowledge. QSAR is a mature technology; however, debate is still active in many topics, in particular about the acceptability of the models and how they are explained. After an excursus in inductive reasoning, we relate the QSAR methodology to open debates in the philosophy of science.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Notes
- 1.
Titus Lucretius Carus, Of The Nature of Things ,
- 2.
- 3.
- 4.
- 5.
References
Hansch C, Maloney PP, Fujita T, Muir RM (1962) Correlation of biological activity of phenoxyacetic acids with hammett substituent constants and partition coefficients. Nature 194:178–180
Hansch C, Fujita T (1964) p-σ-π analysis. A method for the correlation of biological activity and chemical structure. J Am Chem Soc 86:1616–1626
Hansch C (1969) Quantitative approach to biochemical structure-activity relationships. Acc Chem Res 2:232–239
Free SM, Wilson JW (1964) A mathematical contribution to structure-activity studies. J Med Chem 7:395–399
Kier LB, Hall LH, Murray WJ, Randić M (1975) Molecular connectivity I: relationship to non specific local anesthesia. J Pharm Sci 64:1971–1974
Hall LH, Kier LB (1995) Electrotopological state indices for atom types: a novel combination of electronic, topological, and valence state information. J Chem Inf Comput Sci 35:1039–1045
Connolly ML (1985) Computation of molecular volume. J Am Chem Soc 107:1118–1124
Karelson K, Lobanov VS, Katritzky AR (1996) Quantum-chemical descriptors in QSAR/QSPR studies. Chem Rev 96:1027–1044
Wold S, Sjostrom M, Eriksson L (2001) PLS-regression: a basic tool of chemometrics. Chemom Intell Lab Syst 58:109–130
Rogers D, Hopfinger AJ (1994) Application of genetic function approximation to quantitative structure-activity relationships and quantitative structure-property relationships. J Chem Inf Comput Sci 34:854–866
Li L, Hu J, Ho Y-S (2014) Global performance and trend of QSAR/QSPR research: a bibliometric analysis. Mol Inform 33:655–668
Cherkasov A, Muratov EN, Fourches D, Varnek A, Baskin II, Cronin MTD et al (2014) QSAR modeling: where have you been? Where are you going to? J Med Chem 57:4977−5010
Cramer RD, Patterson DE, Bunce JD (1988) Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 110:5959–5967
Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph 20(4):269–276
Gramatica P (2007) Principles of QSAR models validation: internal and external. QSAR Comb Sci 26:694–701
OECD principles for the validation, for regulatory purposes, of (quantitative) structure-activity relationship models. Organization for economic co-operation and development (2004) http://www.oecd.org/env/ehs/risk-assessment/37849783.pdf
José Ayala F, Dobzhansky T (eds) (1974) Studies in the philosophy of biology: reduction and related problems. University of California Press, California
Popper KR (1974) Scientific reduction and the essential incompleteness of all science. In: Ayala FJ, Dobzhansky T (eds) Studies in the philosophy of biology. Palgrave, London
Schummer J (1999) Coping with the growth of chemical knowledge: challenges for chemistry documentation, education, and working chemists. Educación Química 10:92–101
Gòmez Bombarelli R, Duvenaud DK, Hernàndez Lobato JM, Aguilera-Iparraguirre J, Hirzel TD, Adams RP, Aspuru-Guzik A (2016) Automatic chemical design using a data-driven continuous representation of molecules. ACS Central Science, Washington, DC
Gini G, Ferrari T, Cattaneo D, Golbamaki Bakhtyari N, Manganaro A, Benfenati E (2013) Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction. SAR and QSAR Environ Res 24:365–383
Brieman L (2001) Statistical modeling: the two cultures (with comment and a rejoinder by the author). Stat Sci 16:199–231
Rissanen J (1978) Modeling by shortest data description. Automatica 14:465–658
Wolpert D (1996) The lack of a priori distinctions between learning algorithms. Neural Comput 8:1341–1390
Benfenati E, Gini G, Hoffmann S, Luttik R (2010) Comparing in vivo, in vitro, in Silico methods and integrated strategies for chemical assessment: problems and prospects. ATLA 38:153–166
Benfenati E, Gonella Diaza R, Cassano A, Pardoe S, Gini G, Mays C et al (2011) The acceptance of in silico models for REACH. Requirements, barriers, and perspectives. Chem Cent J 5:58
Cronin MTD, Schultz W (2003) Pitfalls in QSAR. J Mol Struct (THEOCHEM) 622:39–51
Alves V, Muratov E, Capuzzi S, Politi R, Low Y, Braga R et al (2016) Alarms about structural alerts. Green Chem 18:4348–4360
Ferrari T, Gini G (2010) An open source multistep model to predict mutagenicity from statistic analysis and relevant structural alerts. Chem Cent J 4(Suppl 1):S2. (online http://www.journal.chemistrycentral.com/content/4/S1/S2)
Gini G, Franchi AM, Manganaro A, Golbamaki A, Benfenati E (2014) ToxRead: a tool to assist in read across and its use to assess mutagenicity of chemicals. SAR QSAR Environ Res 25:999–1011
Benfenati E, Roncaglioni A, Petoumenaou M, Cappelli C, Gini G (2015) Integrating QSAR and read across for environmental assessment. SAR QSAR Environ Res 26:605–618
Rudner R (1953) The scientist qua scientist makes value judgments. Philos Sci 20:1–6
Lovie AD, Lovie P (1986) The flat maximum effect and linear scoring models for prediction. J Forecast 5:159–168
Trout JD, Bishop M (2002) 50 years of successful predictive modeling should be enough: lessons for philosophy of science. Philos Sci 69(S3):S197–S208
Solomonoff RJ (1964) A formal theory of inductive inference: parts 1 and 2. Inf Control 7:1-22–224-254
Suppes P (1962) Models of data. In Studies in the methodology and foundations of science. Selected Papers from 1951 to 1969, Dordrecht, Reidel. pp. 24–35
Hodges W (1997) A shorter model theory. Cambridge University Press, Cambridge
Bailer-Jones DM (2003) When scientific models represent. Int Stud Philos Sci 17:59–74
Giere R (1988) Explaining science: a cognitive approach. University of Chicago Press, Chicago
Cartwright N (1983) How the laws of physics lie. Clarendon Press, Oxford
Hempel CG, Oppenheim P (1948) Studies in the logic of explanation. Philos Sci 15:135–175
Witten H, Frank E (2000) Data mining: practical machine learning tools and techniques with java implementations. Morgan Kaufmann Publishers, London
Benfenati E, Crètien JR, Gini G, Piclin N, Pintore M, Roncaglioni A (2007) Validation of the models. In: Benfenati E (ed) Quantitative structure-activity relationships (QSAR) for pesticides regulatory purposes. Elsevier, Amsterdam, pp 185–200
Gütlein M, Helma C, Karwath A, Kramer S (2013) A large-scale empirical evaluation of cross-validation and external test set validation in (Q)SAR. Mol Inform 32:516–528
Bi J, Bennett K P (2003) Regression error characteristic curves. Procs of the Twentieth international conference on machine learning (ICML-2003), Washington DC
Vapnik VN (1995) The nature of statistical learning theory. Springer-Verlag, Berlin
Polishchuk PG (2017) Interpretation of QSAR models: past, present and future. J Chem Inf Model 57(11):2618–2639
Hartung T (2017) Food for thought. Opinion versus evidence for the need to move away from animal testing. ALTEX 34:193–200
Ulanowicz RE (2009) A third window: natural life beyond Newton and Darwin. Templeton Foundation Press, West Conshohocken
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Gini, G. (2018). QSAR: What Else?. In: Nicolotti, O. (eds) Computational Toxicology. Methods in Molecular Biology, vol 1800. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7899-1_3
Download citation
DOI: https://doi.org/10.1007/978-1-4939-7899-1_3
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-7898-4
Online ISBN: 978-1-4939-7899-1
eBook Packages: Springer Protocols