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How “drug-like” are naturally occurring anti-cancer compounds?

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Abstract

We attempt to evaluate the “drug-likeness” of a collection of ∼1500 natural products, exhibiting in vitro or in vivo activities against cancers of various forms, by using a set of calculated molecular descriptors. Compliance to Lipinski’s “Rule of Five” and Jorgensen’s “Rule of Three” have been used to assess oral availability, by making use of popular parameters like molecular weights, predicted lipophilicities, number of hydrogen bond donors/acceptors, predicted aqueous solubilities, number of primary metabolites and Caco-2 permeabilities. Meanwhile 24 descriptors have been used to predict properties related to the absorption, distribution, metabolism, elimination, and toxicity (ADMET). The ADMET profiles of the anticancer natural products have been analyzed in comparision with the range of properties for 95 % of known drugs. Our results show that the computed parameters fall within the recommended range for about 42 % of the studied compounds, while respectively 63 % and 69 % of the corresponding ‘drug-like’ and ‘lead-like’ subsets had properties predicted to fall within the recommended range for 95 % of known drugs. The aim of giving a picture of how drug-like they are and bring out the need to return to natural sources in searching for anticancer lead compounds.

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Abbreviations

3D:

Three dimensional

ADME/T:

Absorption, distribution, metabolism, excretion, and toxicity

BBB:

Blood brain barrier

CNS:

Central nervous system

DMPK:

Drug metabolism and pharmacokinetics

DNP:

Dictionary of natural products

log P :

Logarithm of the n-octanol/water partition coefficient

MDCK:

Madin-Darby canine kidney

MW:

Molecular weight

NCI:

National Cancer Institute

NP:

Natural product

NPACT:

Naturally Occurring Plant-based Anti-cancer Compound- Activity-Target database

NRB:

Number of rotatable bonds

OPLS:

Optimized potentials for liquid simulations

QSAR:

Quantitative structure-activity relationship

Ro3:

Jorgensen’s “rule of three”

Ro5:

Lipinski’s “rule of five”

SASA:

Solvent accessible surface area

TPSA:

Total polar surface area

VS:

Virtual screening

WHO:

World Health Organisation

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Acknowledgments

Financial support is acknowledged from Lhasa Ltd, Leeds, UK and the academic licence is gratefully acknowledged from Schrodinger Inc., for using the QikProp, Maestro and LigPrep software. The authors acknowledge the support of Drs James A Mbah and Kennedy D Nyongbela of the Chemistry Department, University of Buea, Cameroon.

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Authors and Affiliations

  1. Chemical and Bioactivity Information Centre, Department of Chemistry, Faculty of Science, University of Buea, P. O. Box 63, Buea, Cameroon

    Fidele Ntie-Kang, Lydia L. Lifongo & Simon M. N. Efange

  2. Department of Pharmaceutical Sciences, Martin-Luther University of Halle-Wittenberg, Wolfgang-Langenbeck Str. 4, 06120, Halle (Saale), Germany

    Fidele Ntie-Kang & Wolfgang Sippl

  3. Chemical and Bioactivity Information Centre, 22-23 Blenheim Terrace, Woodhouse Lane, Leeds, LS2 9HD, UK

    Philip N. Judson

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  1. Fidele Ntie-Kang
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  2. Lydia L. Lifongo
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  5. Simon M. N. Efange
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Correspondence to Fidele Ntie-Kang.

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Ntie-Kang, F., Lifongo, L.L., Judson, P.N. et al. How “drug-like” are naturally occurring anti-cancer compounds?. J Mol Model 20, 2069 (2014). https://doi.org/10.1007/s00894-014-2069-z

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