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

• Published in: Journal of molecular modeling Vol. 20; no. 1; p. 2069
• Main Authors: Ntie-Kang, Fidele, Lifongo, Lydia L., Judson, Philip N., Sippl, Wolfgang, Efange, Simon M. N.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2014
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacokinetics; Biological Availability; Blood Proteins - chemistry; Blood-Brain Barrier; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Computer Simulation; Databases, Chemical; Drug Screening Assays, Antitumor; Humans; Hydrogen Bonding; Models, Biological; Molecular Medicine; Molecular Weight; Original Paper; Permeability; Protein Binding; Theoretical and Computational Chemistry; Drug-likeness; Natural products; QSAR; Drug metabolism; In silico; Pharmacokinetics; Cancer
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-014-2069-z

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.