The evolving role of natural products in drug discovery

doi:10.1038/NRD1657

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The evolving role of natural products in drug discovery

Journal Article•DOI•

The evolving role of natural products in drug discovery

01 Mar 2005-Nature Reviews Drug Discovery (Nature Publishing Group)-Vol. 4, Iss: 3, pp 206-220

TL;DR: Recent technological advances that help to address issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening and unrealized expectations from current lead-generation strategies have led to a renewed interest in natural products in drug discovery.

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Abstract: Natural products and their derivatives have historically been invaluable as a source of therapeutic agents. However, in the past decade, research into natural products in the pharmaceutical industry has declined, owing to issues such as the lack of compatibility of traditional natural-product extract libraries with high-throughput screening. However, as discussed in this review, recent technological advances that help to address these issues, coupled with unrealized expectations from current lead-generation strategies, have led to a renewed interest in natural products in drug discovery.

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Journal Article•DOI•

Discovery and resupply of pharmacologically active plant-derived natural products: A review.

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Atanas G. Atanasov¹, Birgit Waltenberger², Eva-Maria Pferschy-Wenzig³, Thomas Linder⁴, Christoph Wawrosch¹, Pavel Uhrin⁵, Veronika Temml², Limei Wang¹, Stefan Schwaiger², Elke H. Heiss¹, Judith M. Rollinger², Judith M. Rollinger¹, Daniela Schuster², Johannes M. Breuss⁵, Valery N. Bochkov³, Marko D. Mihovilovic⁴, Brigitte Kopp¹, Rudolf Bauer³, Verena M. Dirsch¹, Hermann Stuppner² - Show less +16 more•Institutions (5)

University of Vienna¹, University of Innsbruck², University of Graz³, Vienna University of Technology⁴, Medical University of Vienna⁵

01 Dec 2015-Biotechnology Advances

TL;DR: While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs in the future.

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1,760 citations

Cites background or methods from "The evolving role of natural produc..."

...…biological actions due to binding affinities for specific proteins relevant for their biological functions, possess superior chemical diversity and complexity developed during biosynthesis (Clardy and Walsh, 2004; Koehn and Carter, 2005), and often have more advantageous ADME/T properties....
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...A very common approach is to start pharmacological testing with crude plant extracts and subsequently to isolate and characterize the constituents responsible for the activity of the extract (Koehn and Carter, 2005)....
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...…and analytical equipment, increasing number of targets available for testing, and improved possibilities for optimization of natural leads using synthetic modification strategies [reviewed in (Henrich and Beutler, 2013; Koehn and Carter, 2005; Li and Vederas, 2009; Paterson and Anderson, 2005)]....
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...developed during biosynthesis (Clardy and Walsh, 2004; Koehn and Carter, 2005), and often have more advantageous ADME/T properties....
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...programs is common incompatibility of natural products with HTS (Koehn and Carter, 2005)....
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Journal Article•DOI•

Drug Discovery and Natural Products: End of an Era or an Endless Frontier?

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Jesse W.-H. Li¹, John C. Vederas¹•Institutions (1)

University of Alberta¹

10 Jul 2009-Science

TL;DR: Untapped biological resources, “smart screening” methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery.

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Abstract: Historically, the majority of new drugs have been generated from natural products (secondary metabolites) and from compounds derived from natural products. During the past 15 years, pharmaceutical industry research into natural products has declined, in part because of an emphasis on high-throughput screening of synthetic libraries. Currently there is substantial decline in new drug approvals and impending loss of patent protection for important medicines. However, untapped biological resources, "smart screening" methods, robotic separation with structural analysis, metabolic engineering, and synthetic biology offer exciting technologies for new natural product drug discovery. Advances in rapid genetic sequencing, coupled with manipulation of biosynthetic pathways, may provide a vast resource for the future discovery of pharmaceutical agents.

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1,683 citations

Journal Article•DOI•

Drug discovery from medicinal plants.

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Marcy J. Balunas¹, A. Douglas Kinghorn²•Institutions (2)

University of Illinois at Chicago¹, Ohio State University²

22 Dec 2005-Life Sciences

TL;DR: Several compounds from tropical rainforest plant species with potential anticancer activity have been identified and several compounds, mainly from edible plant species or plants used as dietary supplements, that may act as chemopreventive agents are isolated.

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1,591 citations

Cites background from "The evolving role of natural produc..."

...As such, many pharmaceutical companies have eliminated or scaled down their natural product research (Butler, 2004; Koehn and Carter, 2005)....
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..., chiral centers, aromatic rings, complex ring systems, degree of molecule saturation, and number and ratio of heteroatoms) have been shown to be highly relevant to drug discovery efforts (Lee and Schneider, 2001; Feher and Schmidt, 2003; Clardy and Walsh, 2004; Piggott and Karuso, 2004; Koehn and Carter, 2005)....
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...…natural-product-like libraries that combine the features of natural products with combinatorial chemistry (Hall et al., 2001a; Lee and Schneider, 2001; Eldridge et al., 2002; Feher and Schmidt, 2003; Burke et al., 2004; Ganesan, 2004; Piggott and Karuso, 2004; Tan, 2004; Koehn and Carter, 2005)....
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...…aromatic rings, complex ring systems, degree of molecule saturation, and number and ratio of heteroatoms) have been shown to be highly relevant to drug discovery efforts (Lee and Schneider, 2001; Feher and Schmidt, 2003; Clardy and Walsh, 2004; Piggott and Karuso, 2004; Koehn and Carter, 2005)....
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...Because drug discovery from medicinal plants has traditionally been so time-consuming, faster and better methodologies for plant collection, bioassay screening, compound isolation, and compound development must be employed (Do and Bernard, 2004; Koehn and Carter, 2005)....
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Journal Article•DOI•

Privileged Scaffolds for Library Design and Drug Discovery

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Matthew Welsch¹, Scott A. Snyder¹, Brent R. Stockwell¹, Brent R. Stockwell²•Institutions (2)

Columbia University¹, Howard Hughes Medical Institute²

01 Jun 2010-Current Opinion in Chemical Biology

TL;DR: This review explores the concept of using privileged scaffolds to identify biologically active compounds through building chemical libraries by revealing through four selected examples the present state of the art in privileged scaffold library synthesis.

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1,160 citations

Journal Article•DOI•

The exploration of macrocycles for drug discovery--an underexploited structural class.

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Edward M. Driggers, Stephen Hale, Jinbo Lee, Nicholas K. Terrett

01 Jul 2008-Nature Reviews Drug Discovery

TL;DR: This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.

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Abstract: Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.

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1,060 citations

Cites background from "The evolving role of natural produc..."

...Several macrocyclic drugs can be described as having a 'modulator' domain, a sub-region in which the details of molecular structure can be altered without affecting target affinity, but which completes the macrocyclic architecture and positions functional groups for binding (for example the 'spacer' region of the bryostatins...
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References

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Journal Article•DOI•

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

[...]

Christopher A. Lipinski¹, Franco Lombardo¹, Beryl W. Dominy¹, Paul J. Feeney¹•Institutions (1)

Pfizer¹

15 Jan 1997-Advanced Drug Delivery Reviews

TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).

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14,026 citations

Journal Article•DOI•

Natural Products as Sources of New Drugs over the Period 1981−2002

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David J. Newman, Gordon M. Cragg, Kenneth M. Snader

12 Jun 2003-Journal of Natural Products

TL;DR: From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well, and in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame.

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Abstract: This review is an updated and expanded version of a paper that was published in this journal in 1997. The time frame has been extended in both directions to include the 22 years from 1981 to 2002, and a new secondary subdivision related to the natural product source but applied to formally synthetic compounds has been introduced, using the concept of a “natural product mimic” or “NM” to join the original primary divisions. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, the percentage of small molecule, new chemical entities that are nonsynthetic has remained at 62% averaged over the whole time frame. In other areas, the influence of natural product structures is quite marked, particularly in the antihypertensive area, where of the 74 formally synthetic drugs, 48 can be traced to natural product structures/mimics. Similarly, with the 10 antimigraine drugs, seven are bas...

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2,985 citations

Patent•

High throughput screen

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David Geraint Owen, Nicholas Gerard Byrne

14 Jun 1999

TL;DR: In this paper, a high throughput screen for determining the effect of test compounds on ion channel or transporter activity was proposed, and a method for monitoring ion channel activity in a membrane.

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Abstract: The present invention relates to a structure comprising a biological membrane and a porous or perforated substrate, a biological membrane, a substrate, a high throughput screen, methods for production of the structure membrane and substrate, and a method for screening a large number of test compounds in a short period. More particularly it relates to a structure comprising a biological membrane adhered to a porous or perforated substrate, a biological membrane capable of adhering with high resistance seals to a substrate such as perforated glass and the ability to form sheets having predominantly an ion channel or transporter of interest, a high throughput screen for determining the effect of test compounds on ion channel or transporter activity, methods for manufacture of the structure, membrane and substrate, and a method for monitoring ion channel or transporter activity in a membrane.

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2,232 citations

Journal Article•DOI•

Protein kinases--the major drug targets of the twenty-first century?

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Philip Cohen¹•Institutions (1)

University of Dundee¹

01 Apr 2002-Nature Reviews Drug Discovery

TL;DR: A personal view of some of the most important advances that have shaped this field of protein kinases, after G-protein-coupled receptors.

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Abstract: Protein phosphorylation regulates most aspects of cell life, whereas abnormal phosphorylation is a cause or consequence of disease. A growing interest in developing orally active protein-kinase inhibitors has recently culminated in the approval of the first of these drugs for clinical use. Protein kinases have now become the second most important group of drug targets, after G-protein-coupled receptors. Here, I give a personal view of some of the most important advances that have shaped this field.

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2,113 citations

Book•

The practice of medicinal chemistry

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Camille G. Wermuth

09 Aug 2021

TL;DR: Section 1 - General Aspects of Medicinal Chemistry Section 2 - Lead Compound Discovery Strategies Section 3 - Primary Exploration of Structure-Activity Relationships Section 4 - Substituents and Functions: Qualitative and Quantitative aspects of structure- activity Relationships.

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Abstract: General aspects of medicinal chemsitry drug targets and lead compound discovery strategies primary exploration of structure-activity relationships substituents and functions - qualitative and quantitative aspects of structure-activity relationships spatial organization, receptor mapping and molecular modelling chemical modifications influencing the pharmacokinetic properties pharmaceutical and chemical formulation problems development of new drugs - legal and economic aspects.

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1,629 citations