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Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery

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Abstract

Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.

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Abbreviations

ADME:

absorption-distribution-metabolism-excretion

BCUT:

Burden-Chemical Abstract Services–University of Texas

DMSO:

dimethylsulfoxide

e-ADME:

early ADME

HPLC/UV:

high performance liquid chromatography monitored by ultraviolet absorbance

LC-MS:

liquid chromatography–mass spectrometry

MDCK:

Madin-Darby canine kidney

NCI:

National Cancer Institute

PBS:

phosphate buffered saline

PSA:

polar surface area

TEER:

transepithelial electrical resistance

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Authors and Affiliations

  1. Aurigene Discovery Technologies, Ltd., Electronic City Phase 2, 562158, Hosur Road, Bangalore, India

    D.S Samiulla, V. V. Vaidyanathan, P. C. Arun, G. Balan, M. Blaze, S Bondre, G. Chandrasekhar, A. Gadakh, R. Kumar, G. Kharvi, S. Kumar, J. A. Malikayil, M. Moger, M. K. Mone, P Nagarjuna, D. Pendhalkar, A. V. S. Raja Rao, G. Venkateshwar Rao, V. K. Sarma, S. Shaik, G. V. R. Sharma, S. Singh, C. Sreedhar, R. Sonawane & U. Timmanna

  2. Aurigene Discovery Technologies, Inc., 99 Hayden Avenue, Lexington, 02420, Massachusetts, U.S.A.

    H.-O. Kim, C. Ogbu & L. W. Hardy

Authors
  1. D.S Samiulla
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  2. V. V. Vaidyanathan
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  3. P. C. Arun
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  4. G. Balan
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  5. M. Blaze
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  6. S Bondre
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  7. G. Chandrasekhar
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  8. A. Gadakh
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  9. R. Kumar
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  10. G. Kharvi
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  11. H.-O. Kim
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  12. S. Kumar
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  13. J. A. Malikayil
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  14. M. Moger
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  15. M. K. Mone
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  16. P Nagarjuna
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  17. C. Ogbu
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  18. D. Pendhalkar
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  19. A. V. S. Raja Rao
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  20. G. Venkateshwar Rao
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  21. V. K. Sarma
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  22. S. Shaik
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  23. G. V. R. Sharma
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  24. S. Singh
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  25. C. Sreedhar
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  26. R. Sonawane
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  27. U. Timmanna
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  28. L. W. Hardy
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Corresponding author

Correspondence to L. W. Hardy.

Additional information

These authors have contributed equally to this work.

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Samiulla, D., Vaidyanathan, V.V., Arun, P.C. et al. Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery. Mol Divers 9, 131–139 (2005). https://doi.org/10.1007/s11030-005-1297-7

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  • DOI: https://doi.org/10.1007/s11030-005-1297-7

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