Assessment of "drug-likeness" of a small library of natural products using chemoinformatics

Abstract

Even though natural products has an excellent record as a source for new drugs, the advent of ultrahigh-throughput screening and large-scale combinatorial synthetic methods, has caused a decline in the use of natural products research in the pharmaceutical industry. This is due to the efficiency in generating and screening a high number of synthetic combinatorial compounds; whereas traditional natural products based research generate considerably fewer compounds. However, the accelerating throughput caused by these large-scale combinatorial technologies has not resulted in marketed drugs, whereas natural products based research continues to bring new chemical entities to the market. This emphasizes that natures privileged structures have pre-programmed pharmacological activity that can be explored in drug discovery. In addition, not only the size of a chemical library, but also its molecular diversity, biological functionality and “drug-likeness” are important parameters. Natural products are therefore likely to play an important role in future drug discovery programmes, either in pure compound libraries or as scaffolds for combinatorial chemistry. Virtual screening can be used to assess chemical diversity of natural product libraries. As a demonstration of this, a small library of 9 aromadendrane-type sesquiterpenoids was described using this approach. This showed that the library are capable of interacting with the same macromolecular target site containing 4 interaction sites. However, the compounds within the library interacts differently with the interaction sites, which suggests that the compounds could interact with receptor variants or trigger different responses on the same putative receptor. In addition, the physicochemical properties of the compounds in the library vary considerably, which suggests a heterogenity towards possible transport mechanisms in order to access the putative receptor. In conclusion, the heterogeneity in the biological functionality and the molecular diversity of the library shows that natural products indeed are privileged structures offering a pre-programmed range of interaction modes with macro-molecular targets.