Developing a Drug-like Natural Product Library

Abstract

Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs.

Scaffold Flatness: Reversing the Trend

“…The majority (80 %) of NPs possess desirable drug-like properties [45]. In a similar fashion, computer-based analysis revealed that NPs exhibit a remarkable structural diversity of molecular frameworks and scaffolds with desirable drug-like properties rendering them ideal starting points for the design of focused libraries [20].…”

“…Lipinski's ''rule of five'' (Ro5) has been proposed to evaluate the drug-likeness of a chemical compound, based on the physico-chemical properties [33]. About 80 % of NPs have less than two violations of the Ro5 [45]. Overall, NPs are more similar to drugs than compounds obtained from combinatorial synthesis [16].…”

High Throughput Screening Approach to Lead Discovery

“…However, recent comparison studies showed that while natural products do differ from drugs in a number of properties and occupy different regions of chemical space, over 60 percent of those registered in the Dictionary of Natural Products do not violate Ro5 properties [69]. Selected natural-product-derived cores have increasingly been considered as attractive scaffolds for the design of natural products like screening libraries [70]. The role of natural products in modern drug discovery is discussed in Chapter 7.…”

“…Most of these libraries are focused toward a single target, fully exploiting the high resolution of biostructural information [78], although there are also reports of the same principles of SBDD being applied to the design of target family focused libraries [70]. Several approaches are generally employed to leverage biostructural information for library design.…”

NMR Fingerprints of the Drug‐like Natural‐Product Space Identify Iotrochotazine A: A Chemical Probe to Study Parkinson’s Disease

“…[2] This was achieved by analyzing all known compounds that comply with Lipinski’s “rule of five” in the Dictionary of Natural Products, and then targeting species known to contain those metabolites. This study was successful in producing a library in which 85 % of the isolated compounds were Lipinski-compliant and therefore drug-like, however the library was biased towards reported compounds, and contained only a limited number of novel structures (around 1 %).…”