Abstract
Predictive toxicology is a new emerging multifaceted research field aimed at protecting human health and environment from risks posed by chemicals. Such issue is of extreme public relevance and requires a multidisciplinary approach where the experience in medicinal chemistry is of utmost importance. Herein, we will survey some basic recommendations to gather good data and then will review three recent case studies to show how strategies of ligand- and structure-based molecular design, widely applied in medicinal chemistry, can be adapted to meet the more restrictive scientific and regulatory goals of predictive toxicology. In particular, we will report:
-
Docking-based classification models to predict the estrogenic potentials of chemicals.
-
Predicting the bioconcentration factor using biokinetics descriptors.
-
Modeling oral sub-chronic toxicity using a customized k-nearest neighbors (k-NN) approach.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Russell WMS, Burch RL (1959) The principles of humane experimental technique. Johns Hopkins Bloom Sch Public Health, Baltimore
Hornberg JJ, Laursen M, Brenden N et al (2014) Exploratory toxicology as an integrated part of drug discovery. Part I: why and how. Drug Discov Today 19:1131–1136
Nicolotti O, Benfenati E, Carotti A et al (2014) REACH and in silico methods: an attractive opportunity for medicinal chemists. Drug Discov Today 19:1757–1768
Young D, Martin T, Venkatapathy R et al (2008) Are the chemical structures in your QSAR correct? QSAR Comb Sci 27:1337–1345
Zhu H, Tropsha A, Fourches D et al (2008) Combinatorial QSAR modeling of chemical toxicants tested against Tetrahymena pyriformis. J Chem Inf Model 48:766–784
Tetko IV, Sushko I, Pandey AK et al (2008) Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection. J Chem Inf Model 48:1733–1746
Fourches D, Muratov E, Tropsha A (2010) Trust, but verify: on the importance of chemical structure curation in cheminformatics and QSAR modeling research. J Chem Inf Model 50:1189–1204
Maggiora GM (2006) On outliers and activity cliffs—why QSAR often disappoints. J Chem Inf Model 46:1535
Cruz-Monteagudo M, Medina-Franco JL, Pérez-Castillo Y et al (2014) Activity cliffs in drug discovery: Dr Jekyll or Mr Hyde? Drug Discov Today 19:1069–1080
Nicolotti O, Carotti A (2006) QSAR and QSPR studies of a highly structured physicochemical domain. J Chem Inf Model 46:264–276
Todeschini R, Consonni V (eds) (2000) Handbook of molecular descriptors. Wiley, Weinheim
Nicolotti O, Gillet VJ, Fleming PJ et al (2002) Multiobjective optimization in quantitative structure-activity relationships: deriving accurate and interpretable QSARs. J Med Chem 45:5069–5080
Bickerton GR, Paolini GV, Besnard J et al (2012) Quantifying the chemical beauty of drugs. Nat Chem 4:90–98
Bouvier d’Yvoire M, Prieto P, Blaauboer BJ et al (2007) Physiologically-based Kinetic Modelling (PBK Modelling): meeting the 3Rs agenda. The report and recommendations of ECVAM Workshop 63. Altern Lab Anim ATLA 35:661–671
Van de Waterbeemd H, Gifford E (2003) ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2:192–204
Diamanti-Kandarakis E, Bourguignon J-P, Giudice LC et al (2009) Endocrine-disrupting chemicals: an endocrine society scientific statement. Endocr Rev 30:293–342
Shi LM, Fang H, Tong W et al (2001) QSAR models using a large diverse set of estrogens. J Chem Inf Comput Sci 41:186–195
Devillers J, Marchand-Geneste N, Carpy A et al (2006) SAR and QSAR modeling of endocrine disruptors. SAR QSAR Environ Res 17:393–412
Jacobs MN (2004) In silico tools to aid risk assessment of endocrine disrupting chemicals. Toxicology 205:43–53
Trisciuzzi D, Alberga D, Mansouri K et al (2015) Docking-based classification models for exploratory toxicology studies on high-quality estrogenic experimental data. Future Med Chem 7:1921–1936. doi:10.4155/FMC.15.103
Small-molecule drug discovery suite 2014-4: glide, version 6.5 (2014) Schrödinger, LLC, New York
Jones G, Willett P, Glen RC et al (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748
Arnot JA, Gobas FA (2006) A review of bioconcentration factor (BCF) and bioaccumulation factor (BAF) assessments for organic chemicals in aquatic organisms. Environ Rev 14:257–297
OECD (2012) Test no. 305: bioaccumulation in fish: aqueous and dietary exposure, OECD guidelines for the testing of chemicals, section 3. OECD Publishing, 12.10.12, 72. (http://dx.doi.org/10.1787/9789264185296-en). /http://dx.doi.org/10.1787/9789264185296-enS. Consulted July 2015
Gissi A, Gadaleta D, Floris M et al (2014) An alternative QSAR-based approach for predicting the bioconcentration factor for regulatory purposes. ALTEX 31:23–36
Consonni V, Ballabio D, Todeschini R (2009) Comments on the Definition of the Q2 Parameter for QSAR Validation. J Chem Inf Model 49:1669–1678
Schrödinger Release 2011-1: QikProp, version 3.4 (2011) Schrödinger, LLC, New York
Schrödinger Release 2011-1 (2011) Schrödinger, LLC, New York
Jaworska J, Nikolova-Jeliazkova N, Aldenberg T (2005) QSAR applicability domain estimation by projection of the training set descriptor space: a review. Altern Lab Anim ATLA 33:445–459
Aptula AO, Roberts DW (2006) Mechanistic applicability domains for nonanimal-based prediction of toxicological end points: general principles and application to reactive toxicity. Chem Res Toxicol 19:1097–1105
Roberts DW, Aptula AO, Patlewicz G (2006) Mechanistic applicability domains for non-animal based prediction of toxicological endpoints. QSAR analysis of the Schiff base applicability domain for skin sensitization. Chem Res Toxicol 19:1228–1233
Schultz TW, Hewitt M, Netzeva TI et al (2007) Assessing applicability domains of toxicological QSARs: definition, confidence in predicted values, and the role of mechanisms of action. QSAR Comb Sci 26:238–254
Gramatica P (2010) Chemometric methods and theoretical molecular descriptors in predictive QSAR modeling of the environmental behavior of organic pollutants. In: Puzyn T, Leszczynski J, Cronin MT (eds) Recent advances in QSAR studies. Springer, Netherlands, pp 327–366
Sand S, Victorin K, Filipsson AF (2008) The current state of knowledge on the use of the benchmark dose concept in risk assessment. J Appl Toxicol 28:405–421
Sakuratani Y, Zhang HQ, Nishikawa S et al (2013) Hazard Evaluation Support System (HESS) for predicting repeated dose toxicity using toxicological categories. SAR QSAR Environ Res 24:351–363
SCCS—Scientific Committee on Consumer Safety (2012). The SCCS’s notes of guidance for the testing of cosmetics substances and their safety evaluation 8th revision. (http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/ sccs_s_006.pdf). Consulted April 2014
Gadaleta D, Pizzo F, Lombardo A et al (2014) A k-NN algorithm for predicting the oral sub-chronic toxicity in the rat. ALTEX 31:423–432
Cramer RD (2012) The inevitable QSAR renaissance. J Comput Aided Mol Des 26:35–38
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Science+Business Media New York
About this protocol
Cite this protocol
Mangiatordi, G.F., Carotti, A., Novellino, E., Nicolotti, O. (2016). A Round Trip from Medicinal Chemistry to Predictive Toxicology. In: Benfenati, E. (eds) In Silico Methods for Predicting Drug Toxicity. Methods in Molecular Biology, vol 1425. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-3609-0_19
Download citation
DOI: https://doi.org/10.1007/978-1-4939-3609-0_19
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-3607-6
Online ISBN: 978-1-4939-3609-0
eBook Packages: Springer Protocols