Abstract
Principal component analysis (PCA) is a useful tool in the design and planning of chemical libraries. PCA can be used to reveal differences in structural and physicochemical parameters between various classes of compounds by displaying them in a convenient graphical format. Herein, we demonstrate the use of PCA to gain insight into structural features that differentiate natural products, synthetic drugs, natural product-like libraries, and drug-like libraries, and show how the results can be used to guide library design.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Jolliffe IT (2002) Principal component analysis. Springer, New York, NY
Jackson JE (2003) A user’s guide to principal components. Wiley, Hoboken, NJ
Akella LB, DeCaprio D (2010) Cheminformatics approaches to analyze diversity in compound screening libraries. Curr Opin Chem Biol 14:325–330
Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5:993–996
Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75:311–335
Sánchez-Pedregal VM et al (2006) The tubulin-bound conformation of discodermolide derived by NMR studies in solution supports a common pharmacophore model for epothilone and discodermolide. Angew Chem Int Ed 45:7388–7394
Canales A et al (2008) The bound conformation of microtubule-stabilizing agents: NMR insights into the bioactive 3D structure of discodermolide and dictyostatin. Chem Eur J 14:7557–7569
Knust J, Hoffmann RW (2003) Synthesis and conformational analysis of macrocyclic dilactones mimicking the pharmacophore of aplysiatoxin. Helv Chim Acta 86:1871–1893
Khan AR et al (1998) Lowering the entropic barrier for binding conformationally flexible inhibitors to enzymes. Biochemistry 37:16839–16845
Veber DF et al (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623
Rezai T et al (2007) Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J Am Chem Soc 128:2510–2511
Kopp F et al (2012) A diversity-oriented synthesis approach to macrocycles via oxidative ring expansion. Nat Chem Biol 8:358–365
Bauer RA, Wenderski TA, Tan DS (2013) Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion. Nat Chem Biol 9:21–29
Lipinski CA et al (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 23:3–25
Tetko IV et al (2001) Estimation of aqueous solubility of chemical compounds using E-state indices. J Chem Inf Comput Sci 41:1488–1493
Feher M, Schmidt JM (2003) Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci 43:218–227
Lovering F, Bikker J, Humblet C (2009) Escaping from flatland: increasing saturations as an approach to improving clinical success. J Med Chem 52:6752–6756
Clemons PA et al (2010) Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles. Proc Natl Acad Sci U S A 107:18787–18792
O’Shea R, Moser HM (2008) Physicochemical properties of antibacterial compounds: implications for drug discovery. J Med Chem 51:2871–2878
McGrath NA, Brichacek M, Njardarson JT (2010) A graphical journey of innovative organic architectures that have improved our lives. J Chem Educ 87:1348–1349, Also see also: Njardarson Group—Top top-selling drugs Pharmaceuticals poster; http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster
Acknowledgments
We thank Tony D. Davis (MSKCC) for suggesting inclusion of the logD, van der Waals surface area, and relative polar surface area parameters, and for providing modifications of this protocol for Windows users. Instant JChem was generously provided by ChemAxon. Financial support from the NIH (P41 GM076267 to D.S.T., P41 GM076267-03S1 to R.A.B., T32 CA062948-Gudas to T.A.W.), Starr Foundation, Tri-Institutional Stem Cell Initiative, Alfred P. Sloan Foundation (Research Fellowship to D.S.T.), Deutscher Akademischer Austauschdienst (DAAD, postdoctoral fellowship to F.K.), William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, and the MSKCC Experimental Therapeutics Center is gratefully acknowledged.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer Science+Business Media New York
About this protocol
Cite this protocol
Wenderski, T.A., Stratton, C.F., Bauer, R.A., Kopp, F., Tan, D.S. (2015). Principal Component Analysis as a Tool for Library Design: A Case Study Investigating Natural Products, Brand-Name Drugs, Natural Product-Like Libraries, and Drug-Like Libraries. In: Hempel, J., Williams, C., Hong, C. (eds) Chemical Biology. Methods in Molecular Biology, vol 1263. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-2269-7_18
Download citation
DOI: https://doi.org/10.1007/978-1-4939-2269-7_18
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-2268-0
Online ISBN: 978-1-4939-2269-7
eBook Packages: Springer Protocols