The impact of natural products upon modern drug discovery

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In the period 1970–2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the ‘Lipinski universe’ and complies with the Rule of Five. The second is a ‘parallel universe’ that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of log P and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules. We believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more likely than purely synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.

Introduction

Nature has evolved over time to produce a bewildering diversity of secondary metabolites. Based on empirical observations and folklore, natural product extracts were the first, and for a long time, the only medicines available to mankind. Although crude extracts remain the primary healthcare for a majority of the world's population, they are largely supplanted by active pharmaceutical ingredients in the Western world. Furthermore, the dependence upon natural products is no longer obligatory and many drugs are purely synthetic small molecules or manufactured biologics such as vaccines, antibodies, and recombinant proteins. Given these alternatives, there needs to be a rationale for the continued exploration of natural products as leads, and two major arguments can be put forward:

  • Premise 1: Natural products interrogate a different area of chemical space than synthetic compounds.

    If this were untrue, it would be more profitable to concentrate on more readily accessible synthetic compounds. However, there are significant differences in the molecular architecture produced by nature when compared to the synthetic molecules of medicinal chemistry [1••, 2••, 3•, 4••, 5]. Although both aim to produce biologically active matter, biosynthesis operates under a different set of constraints and guiding principles than the synthetic organic chemist (Table 1). In nature, a very parsimonious set of building blocks is utilized, whereas we have access to tens of thousands of commercially available chemicals. As a consequence, we achieve numbers by repeating a reliable sequence of reactions over and over again while changing the input. Nature, on the contrary, diversifies by taking its limited building blocks and partitioning them into a multitude of pathways. Further differences occur in the type of synthetic transformation performed. Nature is oxophilic, and has developed enzymes that exquisitely accomplish site-selective Csingle bondH activation [6••, 7•] to introduce oxygen and discriminate between numerous functional groups at different oxidation levels. Meanwhile, medicinal chemistry concentrates on nitrogen and often includes ancillary atoms such as sulfur and halogens that are relatively rare in nature. Finally, the chiral enzymes of biosynthesis usually yield the product as a single stereoisomer. Although medicinal chemists are themselves chiral and target chiral enzymes or receptors, they prefer to work in ‘flatland’ with molecules low in stereochemical features.

  • Premise 2: Natural products are amenable to further improvement.

    If this were untrue, the natural product extracts would suffice, or the purified natural product would become the final drug without modification. Although this can often be the case, it runs counter to the drug discovery paradigm where initial leads are subjected to extensive medicinal chemistry campaigns before a candidate is selected. A priori, natural products should undergo the same iterative cycle of improvement, as their evolutionary reason for existence is not for use as a therapeutic agent. Thus, one can expect that the natural product can be further improved, whether in terms of efficacy and selectivity for the target or achieving optimal pharmacokinetic and pharmacodynamic properties. For example, the opium alkaloid morphine is an important drug that is obtained solely from nature and continues to be used in both extract and pure form. At the same time, morphine has encouraged the discovery of many semisynthetic and fully synthetic compounds based on the same pharmacophore that are successful second-generation opioid drugs.

Section snippets

The molecular architecture of drug-like matter

Biological space is modest in size  the human genome is on the order of 3 × 104 genes of which only a fraction is targeted by current therapeutics [8, 9•]. Meanwhile, chemical space is infinite, and there are an estimated [10] 1060 organic compounds with a molecular weight cutoff of 500. Our imperfect understanding of which areas of chemical space are best suited to interact with biological space is the major bottleneck of drug discovery. In recent years, there were various attempts at narrowing

The molecular architecture of successful natural products

How many marketed drugs have a natural product origin, or are based on a pharmacophore first identified in a natural product? This question is easy to answer, thanks to the excellent and comprehensive surveys by Newman at the National Cancer Institute (NCI). The most recent survey [17••], covering the period 1981–June 2006, lists a total of 1184 new chemical entities (NCEs) receiving approval. Of these, 52% have a natural product connection, 18% are biologics, and 30% purely synthetic. The

Rules for successful natural products

Tens of thousands of biologically active natural products were discovered in the period 1970–2006. Yet, only 24 of these had the ‘right stuff’ that resulted in an approved drug [19]. On the basis of the data in the preceding section, we can devise some guiding principles that will help in assessing the worth of natural product leads (or indeed synthetic compounds as well) as potential therapeutic agents.

Is the glass half empty or half full?

The 35-year period 1970–2006 witnessed 24 natural products leads culminating in an approved drug  is this a reasonable rate of return? The answer will depend on whether one is a proponent of natural products or not. Naysayers will declare that 20-odd drugs is a poor return for the amount of resource expended globally for the past 30 years in natural product drug discovery. The pro-natural products community will point to the same number as a success, as natural product screening delivered nearly

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The data in Table 2, Table 3, Table 4 were first presented at the Zing conference, Small Molecule Drug Discovery: From Early-stage to the Clinic, Antigua, 17–20 January 2008. I am especially grateful to the following for their helpful comments and discussions: Drs Lilian Alcaraz, Andrew Davis and Paul Leeson (all at AstraZeneca), Miles Congreve (Astex), János Fischer (Gedeon Richter), Paul Fish (Pfizer), Chris Larson (Exelixis), Emanuele Perola (Vertex) and John Proudfoot (Boehringer-Ingelheim).

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