Computational toxicology: Its essential role in reducing drug attrition

Human and Experimental Toxicology

Volumn 34, Issue 12, 2015, Pages 1304-1309

  Naven, R T ^a   Louise May, S ^b  

^a PFIZER INC   (United States)

^b NewWave Consulting LLC   (United States)

Author keywords

computational toxicology; investigative toxicology; predictive toxicology; QSAR; Structure activity relationship (SAR)

Indexed keywords

NEFAZODONE; NEW DRUG; PRODRUG; XIMELAGATRAN;

ARTICLE; CELL MEMBRANE; CYTOTOXICITY; DELAYED HYPERSENSITIVITY; DRUG EXPOSURE; DRUG INDUSTRY; DRUG SAFETY; HUMAN; IN VITRO STUDY; IN VIVO STUDY; KNOWLEDGE; LIPIDOSIS; LIPOPHILICITY; LIVER TOXICITY; MUTAGENICITY; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PHYSICAL CHEMISTRY; PRIORITY JOURNAL; RISK ASSESSMENT; STRUCTURE ACTIVITY RELATION; ADVERSE DRUG REACTION; BIOLOGICAL MODEL; BIOLOGY; COMPUTER SIMULATION; PROCEDURES; TOXICOLOGY;

COMPUTATIONAL BIOLOGY; COMPUTER SIMULATION; DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS; HUMANS; MODELS, BIOLOGICAL; TOXICOLOGY;

EID: 84948704233     PISSN: 09603271     EISSN: 14770903     Source Type: Journal    
DOI: 10.1177/0960327115605440     Document Type: Article

References (19)

1. Hornberg JJ, Laursen M, Brenden N, et al. Exploratory toxicology as an integrated part of drug discovery. Part II: screening strategies. Drug Discov Today 2014; 19: 1137-1144.
2. Hornberg JJ, Laursen M, Brenden N, et al. Exploratory toxicology as an integrated part of drug discovery. Part I: why and how. Drug Discov Today 2014; 19: 1131-1136.
3. Dykens JA, Jamieson JD, Marroquin LD, et al. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 2008; 103: 335-345.
4. Stepan AF, Walker DP, Bauman J, et al. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol 2011; 24: 1345-1410.
5. Kalgutkar AS, Vaz AD, Lame ME, et al. Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos 2005; 33: 243-253.
6. Robinson DS, Marcus RN, Archibald DG, et al. Therapeutic dose range of nefazodone in the treatment of major depression. J Clin Psychiatry 1996; 57 (Suppl 2): 6-9.
7. Kalgutkar AS, Dalvie D,. Predicting toxicities of reactive metabolite-positive drug candidates. Ann Rev Pharmacol Toxicol 2015; 55: 35-54.
8. Keisu M, Andersson TB,. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol 2010; 196: 407-418.
9. Benigni R, Netzeva TI, Benfenati E, et al. The expanding role of predictive toxicology: an update on the (Q)SAR models for mutagens and carcinogens. J Environ Sci Health C, Environ Carcinogen Ecotoxicol Rev 2007; 25: 53-97.
10. Spycher S, Smejtek P, Netzeva TI, et al. Toward a class-independent quantitative structure-activity relationship model for uncouplers of oxidative phosphorylation. Chem Res Toxicol 2008; 21: 911-927.
11. Hughes JD, Blagg J, Price DA, et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett 2008; 18: 4872-4875.
12. Muthas D, Boyer S, Hasselgren C,. A critical assessment of modeling safety-related drug attrition. Med Chem Commun 2013; 4: 1058-1065.
13. Tarcsay Á Keserú GM,. Contributions of molecular properties to drug promiscuity. J Med Chem 2013; 56: 1789-1795.
14. Price DA, Blagg J, Jones L, et al. Physicochemical drug properties associated with in vivo toxicological outcomes: a review. Exp Opin Drug Metab Toxicol 2009; 5: 921-931.
15. Elangbam CS,. Drug-induced valvulopathy: an update. Toxicol Pathol 2010; 38: 837-848.
16. Shah F, Louise-May S, Greene N,. Chemotypes sensitivity and predictivity of in vivo outcomes for cytotoxic assays in THLE and HepG2 cell lines. Bioorg Med Chem Lett 2014; 24: 2753-2757.
17. Kakiuchi-Kiyota S, Naven R, DeSilver D, et al. Evaluation of an in vitro cytotoxicity assay in fbs-free medium to select safer compounds. Toxicologist 2015.
18. Nadanaciva S, Yvonne W,. New insights in drug-induced mitochondrial toxicity. Curr Pharm Des 2011; 17: 2100-2112.
19. Naven RT, Swiss R, Klug-McLeod J, et al. The development of structure-activity relationships for mitochondrial dysfunction: uncoupling of oxidative phosphorylation. Toxicol Sci 2013; 131: 271-278.