Introduction: Even though there have been substantial advances in our understanding of biological systems, research in drug discovery is only just now beginning to utilize this type of information. The single-target paradigm, which exemplifies the reductionist approach, remains a mainstay of drug research today. A deeper view of the complexity involved in drug discovery is necessary to advance on this field. Areas covered: This perspective provides a summary of research areas where cheminformatics has played a key role in drug discovery, including of the available resources as well as a personal perspective of the challenges still faced in the field. Expert opinion: Although great strides have been made in the handling and analysis of biological and pharmacological data, more must be done to link the data to biological pathways. This is crucial if one is to understand how drugs modify disease phenotypes, although this will involve a shift from the single drug/single target paradigm that remains a mainstay of drug research. Moreover, such a shift would require an increased awareness of the role of physiology in the mechanism of drug action, which will require the introduction of new mathematical, computer, and biological methods for chemoinformaticians to be trained in.

Natural products are an invaluable source of molecules with a large variety of biological activities. Interest in natural products in drug discovery is documented in an increasing number of publications of bioactive secondary metabolites. Among those, medicinal plants are one of the most studied for this endeavor. An ever thriving area of opportunity within the field concerns the discovery of antidiabetic natural products. As a result, a vast amount of secondary metabolites are isolated from medicinal plants used against diabetes mellitus but whose information has not been organized systematically yet. Several research articles enumerate antidiabetic compounds, but the lack of a chemical database for antidiabetic metabolites limits their application in drug development. In this work, we present DiaNat-DB, a comprehensive collection of 336 molecules from medicinal plants reported to have in vitro or in vivo antidiabetic activity. We also discuss a chemoinformatic analysis of DiaNat-DB to compare antidiabetic drugs and natural product databases. To further explore the antidiabetic chemical space based on DiaNat compounds, we searched for analogs in ZINC15, an extensive database listing commercially available compounds. This work will help future analyses, design, and development of new antidiabetic drugs. DiaNat-DB and its ZINC15 analogs are freely available at http://rdu.iquimica.unam.mx/handle/20.500.12214/1186.

A new malbrancheamide analogue, isomalbrancheamide B (3), along with three known compounds, malbrancheamide (1), isomalbrancheamide (2), and premalbrancheamide (4), were isolated in higher yields from the alkaloid fraction of the fungus Malbranchea aurantiaca. The interaction of the alkaloids 1–4 with calmodulin (CaM) was analyzed using different enzymatic, fluorescence, spectroscopic, nuclear magnetic resonance (NMR), and molecular modelling techniques. On the basis of the enzymatic and fluorescence experiments, malbrancheamides 1–3 are classical CaM inhibitors. Compound 4, however, did not quench the extrinsic fluorescence of the CaM biosensor indicating that it could be a functional inhibitor. Circular dichroism, NMR, and molecular modelling studies revealed that 1 binds to CaM in the same hydrophobic pocket than the chlorpromazine and trifluoperazine, two classical CaM inhibitors. Thus, malbrancheamide and related monochlorinated analogues are compounds with a high potential for the development of new therapeutic agents, involving CaM as their molecular target.