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1.  Biodiversity conservation and drug discovery: Can they be combined? The Suriname and Madagascar experiences 
Pharmaceutical biology  2009;47(8):809-823.
The approach to new drugs through natural products has proved to be the single most successful strategy for the discovery of new drugs, but in recent years its use has been deemphasized by many pharmaceutical companies in favor of approaches based on combinatorial chemistry and genomics, among others.
Drug discovery from natural sources requires continued access to plant, marine, and microbial biomass, and so the preservation of tropical rainforests is an important part of our drug discovery program. Sadly, many of the tropical forests of the world are under severe environmental pressure, and deforestation is a serious problem in most tropical countries. One way to combat this loss is to demonstrate their value as potential sources of new pharmaceutical or agrochemical products.
As part of an effort to integrate biodiversity conservation and drug discovery with economic development, we initiated an International Cooperative biodiversity Group (ICBG) to discover potential pharmaceuticals from the plant biodiversity of Suriname and Madagascar. The Group, established with funding from agencies of the United States government, involved participants from the USA, Suriname, and Madagascar. The basic approach was to search for bioactive plants in the Suriname and Malagasy flora, and to isolate their bioactive constituents by the best available methods, but the work included capacity building as well as research. Progress on this project will be reported, drawing on results obtained from the isolation of bioactive natural products from Suriname and Madagascar. The benefits of this general approach to biodiversity and drug discovery will also be discussed.
PMCID: PMC2746688  PMID: 20161050
Suriname; Madagascar; biodiversity conservation; bioactive compounds; alkaloids; cardenolides; terpenoids; marine metabolites
2.  New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics 
With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.
PMCID: PMC3619623  PMID: 23634172
3.  Boesenbergia rotunda: From Ethnomedicine to Drug Discovery 
Boesenbergia rotunda is a herb from the Boesenbergia genera under the Zingiberaceae family. B. rotunda is widely found in Asian countries where it is commonly used as a food ingredient and in ethnomedicinal preparations. The popularity of its ethnomedicinal usage has drawn the attention of scientists worldwide to further investigate its medicinal properties. Advancement in drug design and discovery research has led to the development of synthetic drugs from B. rotunda metabolites via bioinformatics and medicinal chemistry studies. Furthermore, with the advent of genomics, transcriptomics, proteomics, and metabolomics, new insights on the biosynthetic pathways of B. rotunda metabolites can be elucidated, enabling researchers to predict the potential bioactive compounds responsible for the medicinal properties of the plant. The vast biological activities exhibited by the compounds obtained from B. rotunda warrant further investigation through studies such as drug discovery, polypharmacology, and drug delivery using nanotechnology.
PMCID: PMC3519102  PMID: 23243448
4.  Decline in new drug launches: myth or reality? Retrospective observational study using 30 years of data from the UK 
BMJ Open  2013;3(2):e002088.
To describe trends in new drugs launched in the UK from 1982 to 2011 and test the hypothesis that the rate of new drug introductions has declined over the study period. There is wide concern that pharmaceutical innovation is declining. Reported trends suggest that fewer new drugs have been launched over recent decades, despite increasing investment into research and development.
Retrospective observational study.
Setting and data source
Database of new preparations added annually to the British National Formulary (BNF).
Main outcome measures
The number of new drugs entered each year, including new chemical entities(NCEs) and new biological drugs, based on first appearance in the BNF.
There was no significant linear trend in the number of new drugs introduced into the UK from 1982 to 2011. Following a dip in the mid-1980s (11–12 NCEs/new biologics introduced annually from 1985 to 1987), there was a variable increase in the numbers of new drugs introduced annually to a peak of 34 in 1997. This peak was followed by a decline to approximately 20 new drugs/year between 2003 and 2006, and another peak in 2010. Extending the timeline further back with existing published data shows an overall slight increase in new drug introductions of 0.16/year over the entire 1971 to 2011 period.
The purported ‘innovation dip’ is an artefact of the time periods previously studied. Reports of declining innovation need to be considered in the context of their timescale and perspective.
PMCID: PMC3585972  PMID: 23427198
Innovation; Pharmaceutical; New drugs; Drug launches; United Kingdom
5.  Phenocopy – A Strategy to Qualify Chemical Compounds during Hit-to-Lead and/or Lead Optimization 
PLoS ONE  2010;5(12):e14272.
A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems with new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor β Receptor I (TGF-βR1) were qualified by high-throughput RNA expression profiling. This chemical genomics approach resulted in a precise time-dependent insight to the TGF-β biology and allowed furthermore a comprehensive analysis of each NCE's off-target effects. The evaluation of off-target effects by the phenocopy approach allows a more accurate and integrated view on optimized compounds, supplementing classical biological evaluation parameters such as potency and selectivity. It has therefore the potential to become a novel method for ranking compounds during various drug discovery phases.
PMCID: PMC3000806  PMID: 21170314
6.  Current approaches toward production of secondary plant metabolites 
Plants are the tremendous source for the discovery of new products with medicinal importance in drug development. Today several distinct chemicals derived from plants are important drugs, which are currently used in one or more countries in the world. Secondary metabolites are economically important as drugs, flavor and fragrances, dye and pigments, pesticides, and food additives. Many of the drugs sold today are simple synthetic modifications or copies of the naturally obtained substances. The evolving commercial importance of secondary metabolites has in recent years resulted in a great interest in secondary metabolism, particularly in the possibility of altering the production of bioactive plant metabolites by means of tissue culture technology. Plant cell and tissue culture technologies can be established routinely under sterile conditions from explants, such as plant leaves, stems, roots, and meristems for both the ways for multiplication and extraction of secondary metabolites. In vitro production of secondary metabolite in plant cell suspension cultures has been reported from various medicinal plants, and bioreactors are the key step for their commercial production. Based on this lime light, the present review is aimed to cover phytotherapeutic application and recent advancement for the production of some important plant pharmaceuticals.
PMCID: PMC3283951  PMID: 22368394
Cell suspension culture; medicinal plants; plant pharmaceuticals; secondary metabolites
7.  Nature's Medicines: Traditional Knowledge and Intellectual Property Management. Case Studies from the National Institutes of Health (NIH), USA 
With the emergence and re-emergence of infectious diseases and development of multi-drug resistance, there is a dire need to find newer cures and to produce more drugs and vaccines in the pipeline. To meet these increasing demands biomedical researchers and pharmaceutical companies are combining advanced methods of drug discovery, such as combinatorial chemistry, high-throughput screening and genomics, with conventional approaches using natural products and traditional knowledge. However, such approaches require much international cooperation and understanding of international laws and conventions as well as local customs and traditions. This article reviews the forty years of cumulative experience at the National Institutes of Health (initiated by the National Cancer Institute) in natural products drug discovery. It presents (1) three major cooperative programs (2) the legal mechanisms for cooperation and (3) illustrative case studies from these programs. We hope that these discussions and our lessons learned would be helpful to others seeking to develop their own models of cooperation for the benefit of global health.
PMCID: PMC2739453  PMID: 16475917
8.  Biological screening of natural products and drug innovation in China 
Natural products have been applied to human healthcare for thousands of years. Drug discovery in ancient times was largely by chance and based on clinical practices. As understanding of therapeutic benefits deepens and demands for natural products increase, previously serendipitous discoveries evolve into active searches for new medicines. Many drugs presently prescribed by physicians are either directly isolated from plants or are artificially modified versions of natural products. Scientists are looking for lead compounds with specific structures and pharmacological effects often from natural sources. Experiences and successes of Chinese scientists in this specialized area have resulted in a number of widely used drugs. The tremendous progress made in life sciences has not only revealed many pathological processes of diseases, but also led to the establishment of various molecular and cellular bioassays in conjunction with high-throughput technologies. This is advantageous and permits certain natural compounds that are difficult to isolate and purify, and compounds that are difficult to synthesize, to be assayed. The transition from traditional to empirical and to molecular screening will certainly increase the probability of discovering new leads and drug candidates from natural products.
PMCID: PMC2435573  PMID: 17317643
natural products; traditional Chinese medicine; drug screening; high-throughput technologies; clinical trial; therapeutics
9.  Chemistry and Biology of the Caged Garcinia Xanthones 
Natural products have been a great source of many small molecule drugs for various diseases. In spite of recent advances in biochemical engineering and fermentation technologies that allow us to explore microorganisms and the marine environment as alternative sources of drugs, more than 70% of the current small molecule therapeutics derive their structures from plants used in traditional medicine. Natural-product-based drug discovery relies heavily on advances made in the sciences of biology and chemistry. Whereas biology aims to investigate the mode of action of a natural product, chemistry aims to overcome challenges related to its supply, bioactivity, and target selectivity. This review summarizes the explorations of the caged Garcinia xanthones, a family of plant metabolites that possess a unique chemical structure, potent bioactivities, and a promising pharmacology for drug design and development.
PMCID: PMC3144150  PMID: 20648491
cyclic compounds; cycloaddition; domino reactions; natural products; synthesis design
Rapid advances in biomedical sciences in recent years have drastically accelerated the discovery of the molecular basis of human diseases. The great challenge is how to translate the newly acquired knowledge into new medicine for disease prevention and treatment. Drug discovery is a long and expensive process and the pharmaceutical industry has not been very successful at it despite its enormous resources and spending on the process. It is increasingly realized that academic biomedical research institutions ought to be engaged in early stage drug discovery, especially when it can be coupled to their basic research. To leverage the productivity of new drug development a substantial acceleration in validation of new therapeutic targets is required, which would require small molecules that can precisely control target functions in complex biological systems in a temporal and dose-dependent manner. In this review, we describe a process of integration of small molecule discovery and chemistry in academic biomedical research, which will ideally bring together the elements of innovative approaches to new molecular targets; existing basic and clinical research; screening infrastructure; and synthetic and medicinal chemistry to follow-up on small molecule hits. Such integration of multi-disciplinary resources and expertise will enable academic investigators to discover novel small molecules that are expected to facilitate their efforts in both mechanistic research and new drug target validation. More broadly academic drug discovery should contribute new entities to therapy for intractable human diseases especially for orphan diseases, and hopefully stimulate and synergize with the commercial sector.
PMCID: PMC2917822  PMID: 20687180
Small molecule; drug discovery; chemical screening; medicinal chemistry
11.  Novel Chemical Space Exploration via Natural Products 
Journal of medicinal chemistry  2009;52(7):1953-1962.
Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notable in coverage of chemical space, and tangible lead-like NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbours of approved drugs. Several of the NPs revealed by this method, were confirmed to exhibit the same activity as their drug neighbours. The identification of leads from a NP starting point may prove a useful strategy for drug discovery, in the search for novel leads with unique properties.
PMCID: PMC2696019  PMID: 19265440
12.  Managing laboratory automation: integration and informatics in drug discovery 
Drug discovery today requires the focused use of laboratory automation and other resources in combinatorial chemistry and high-throughput screening (HTS). The ultimate value of both combinatorial chemistry and HTS technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of the drug discovery processes-informatics is key to this success. This presentation focuses on informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years are described.
PMCID: PMC2562837  PMID: 18924689
13.  Integrated Dataset of Screening Hits against Multiple Neglected Disease Pathogens 
New chemical entities are desperately needed that overcome the limitations of existing drugs for neglected diseases. Screening a diverse library of 10,000 drug-like compounds against 7 neglected disease pathogens resulted in an integrated dataset of 744 hits. We discuss the prioritization of these hits for each pathogen and the strong correlation observed between compounds active against more than two pathogens and mammalian cell toxicity. Our work suggests that the efficiency of early drug discovery for neglected diseases can be enhanced through a collaborative, multi-pathogen approach.
Author Summary
The search for new drugs for human neglected diseases accelerated in the past decade, based on the recognition that addressing these infections was necessary for global poverty reduction. The expansion of discovery and development programmes was supported by donor investment, increasing participation of the industry and the creation of Product Development Partnership (PDP) enterprises. Despite these efforts, major discovery gaps remain as, apart from some repurposed drugs and a few new molecules for malaria, no new candidate has been recently transitioned from discovery into development for the major Neglected Tropical Diseases (NTDs). In this publication, we present a collaborative network model for drug discovery based on coordinated North-South partnerships. This network carried out low-to-medium throughput whole-organism screening assays against seven NTDs (malaria, leishmaniasis, human African trypanosomiasis [HAT], Chagas' disease, schistosomiasis, onchocerciasis and lymphatic filariasis) together with an early assessment of compound toxicity in mammalian cells. We describe a screening campaign of 10,000 molecules, its outcome and the implications of this strategy for enhancing the efficiency and productivity of drug discovery for NTDs.
PMCID: PMC3243694  PMID: 22247786
14.  Genome-Based Studies of Marine Microorganisms to Maximize the Diversity of Natural Products Discovery for Medical Treatments 
Marine microorganisms are rich source for natural products which play important roles in pharmaceutical industry. Over the past decade, genome-based studies of marine microorganisms have unveiled the tremendous diversity of the producers of natural products and also contributed to the efficiency of harness the strain diversity and chemical diversity, as well as the genetic diversity of marine microorganisms for the rapid discovery and generation of new natural products. In the meantime, genomic information retrieved from marine symbiotic microorganisms can also be employed for the discovery of new medical molecules from yet-unculturable microorganisms. In this paper, the recent progress in the genomic research of marine microorganisms is reviewed; new tools of genome mining as well as the advance in the activation of orphan pathways and metagenomic studies are summarized. Genome-based research of marine microorganisms will maximize the biodiscovery process and solve the problems of supply and sustainability of drug molecules for medical treatments.
PMCID: PMC3151524  PMID: 21826184
15.  Trends in the Discovery of New Marine Natural Products from Invertebrates over the Last Two Decades – Where and What Are We Bioprospecting? 
PLoS ONE  2012;7(1):e30580.
It is acknowledged that marine invertebrates produce bioactive natural products that may be useful for developing new drugs. By exploring untapped geographical sources and/or novel groups of organisms one can maximize the search for new marine drugs to treat human diseases. The goal of this paper is to analyse the trends associated with the discovery of new marine natural products from invertebrates (NMNPI) over the last two decades. The analysis considers different taxonomical levels and geographical approaches of bioprospected species. Additionally, this research is also directed to provide new insights into less bioprospected taxa and world regions. In order to gather the information available on NMNPI, the yearly-published reviews of Marine Natural Products covering 1990–2009 were surveyed. Information on source organisms, specifically taxonomical information and collection sites, was assembled together with additional geographical information collected from the articles originally describing the new natural product. Almost 10000 NMNPI were discovered since 1990, with a pronounced increase between decades. Porifera and Cnidaria were the two dominant sources of NMNPI worldwide. The exception was polar regions where Echinodermata dominated. The majority of species that yielded the new natural products belong to only one class of each Porifera and Cnidaria phyla (Demospongiae and Anthozoa, respectively). Increased bioprospecting efforts were observed in the Pacific Ocean, particularly in Asian countries that are associated with the Japan Biodiversity Hotspot and the Kuroshio Current. Although results show comparably less NMNPI from polar regions, the number of new natural products per species is similar to that recorded for other regions. The present study provides information to future bioprospecting efforts addressing previously unexplored taxonomic groups and/or regions. We also highlight how marine invertebrates, which in some cases have no commercial value, may become highly valuable in the ongoing search for new drugs from the sea.
PMCID: PMC3262841  PMID: 22276216
16.  Drug discovery from Nature: automated high-quality sample preparation 
Secondary metabolites from plants, animals and microorganisms have been proven to be an outstanding source for new and innovative drugs and show a striking structural diversity that supplements chemically synthesized compounds or libraries in drug discovery programs. Unfortunately, extracts from natural sources are usually complex mixtures of compounds:: often generated in time consuming and for the most part manual processes. As quality and quantity of the provided samples play a pivotal role in the success of high-throughput screening programs this poses serious problems. In order to make samples of natural origin competitive with synthetic compound libraries, we devised a novel, automated sample preparation procedure based on solid-phase extraction (SPE). By making use of a modified Zymark RapidTrace® SPE workstation an easy-to-handle and effective fractionation method has been developed which allows the generation of highquality samples from natural origin, fulfilling the requirements of an integration into high-throughput screening programs.
PMCID: PMC2562846  PMID: 18924703
17.  Discovery and Development of Natural Product-derived Chemotherapeutic Agents Based on a Medicinal Chemistry Approach⊥† 
Journal of natural products  2010;73(3):500-516.
Medicinal plants have long been an excellent source of pharmaceutical agents. Accordingly, the long term objectives of the author's research program are to discover and design new chemotherapeutic agents based on plant-derived compound leads by using a medicinal chemistry approach, which is a combination of chemistry and biology. Different examples of promising bioactive natural products and their synthetic analogs, including sesquiterpene lactones, quassinoids, naphthoquinones, phenylquinolones, dithiophenediones, neo-tanshinlactone, tylophorine, suksdorfin, DCK, and DCP, will be presented with respect to their discovery and preclinical development as potential clinical trial candidates. Research approaches include bioactivity- or mechanism of action-directed isolation and characterization of active compounds, rational drug design-based modification and analog synthesis, as well as structure-activity relationship and mechanism of action studies. Current clinical trials agents discovered by the Natural Products Research Laboratories, University of North Carolina, include bevirimat (dimethyl succinyl betulinic acid), which is now in Phase IIb trials for treating AIDS. Bevirimat is also the first in a new class of HIV drug candidates called “maturation inhibitors”. In addition, an etoposide analog, GL-331, progressed to anticancer Phase II clinical trials, and the curcumin analog JC-9 is in Phase II clinical trials for treating acne and in development for trials against prostate cancer. The discovery and development of these clinical trials candidates will also be discussed.
PMCID: PMC2893734  PMID: 20187635
18.  Database on pharmacophore analysis of active principles, from medicinal plants 
Bioinformation  2010;5(2):43-45.
Plants continue to be a major source of medicines, as they have been throughout human history. In the present days, drug discovery from plants involves a multidisciplinary approach combining ethnobotanical, phytochemical and biological techniques to provide us new chemical compounds (lead molecules) for the development of drugs against various pharmacological targets, including cancer, diabetes and its secondary complications. In view of this need in current drug discovery from medicinal plants, here we describe another web database containing the information of pharmacophore analysis of active principles possessing antidiabetic, antimicrobial, anticancerous and antioxidant properties from medicinal plants. The database provides the botanical, taxonomic classification, biochemical as well as pharmacological properties of medicinal plants. Data on antidiabetic, antimicrobial, anti oxidative, anti tumor and anti inflammatory compounds, and their physicochemical properties, SMILES Notation, Lipinski's properties are included in our database. One of the proposed features in the database is the predicted ADMET values and the interaction of bioactive compounds to the target protein. The database alphabetically lists the compound name and also provides tabs separating for anti microbial, antitumor, antidiabetic, and antioxidative compounds.
Availability /
PMCID: PMC3039985  PMID: 21346859
medicinal plants database; anti-diabetic compounds; antioxidant compounds; antimicrobial compounds; anticarcinogenic compounds; ADMET properties; pharmacophore analysis
19.  Drug Discovery for Neglected Diseases: Molecular Target-Based and Phenotypic Approaches 
Journal of Medicinal Chemistry  2013;56(20):7719-7726.
Drug discovery for neglected tropical diseases is carried out using both target-based and phenotypic approaches. In this paper, target-based approaches are discussed, with a particular focus on human African trypanosomiasis. Target-based drug discovery can be successful, but careful selection of targets is required. There are still very few fully validated drug targets in neglected diseases, and there is a high attrition rate in target-based drug discovery for these diseases. Phenotypic screening is a powerful method in both neglected and non-neglected diseases and has been very successfully used. Identification of molecular targets from phenotypic approaches can be a way to identify potential new drug targets.
PMCID: PMC3954685  PMID: 24015767
20.  Microbial Strain Prioritization Using Metabolomics Tools for the Discovery of Natural Products 
Analytical Chemistry  2012;84(10):4277-4283.
Natural products profoundly impact many research areas, including medicine, organic chemistry, and cell biology. However, discovery of new natural products suffers from a lack of high throughput analytical techniques capable of identifying structural novelty in the face of a high degree of chemical redundancy. Methods to select bacterial strains for drug discovery have historically been based on phenotypic qualities or genetic differences and have not been based on laboratory production of secondary metabolites. Therefore, untargeted LC/MS-based secondary metabolomics was evaluated to rapidly and efficiently analyze marine-derived bacterial natural products using LC/MS-principal component analysis (PCA). A major goal of this work was to demonstrate that LC/MS-PCA was effective for strain prioritization in a drug discovery program. As proof of concept, we evaluated LC/MS-PCA for strain selection to support drug discovery, for the discovery of unique natural products, and for rapid assessment of regulation of natural product production.
PMCID: PMC3352271  PMID: 22519562
21.  The continuing search for antitumor agents from higher plants 
Phytochemistry letters  2010;3(1):1-8.
Plant secondary metabolites and their semi-synthetic derivatives continue to play an important role in anticancer drug therapy. In this short review, selected single chemical entity antineoplastic agents from higher plants that are currently in clinical trials as cancer chemotherapy drug candidates are described. These compounds are representative of a wide structural diversity. In addition, the approaches taken toward the discovery of anticancer agents from tropical plants in the laboratory of the authors are summarized. The successful clinical utilization of cancer chemotherapeutic agents from higher plants has been evident for about half a century, and, when considered with the promising pipeline of new plant-derived compounds now in clinical trials, this augurs well for the continuation of drug discovery research efforts to elucidate additional candidate substances of this type.
PMCID: PMC2836022  PMID: 20228943
Higher plants; secondary metabolites; anticancer agents; compounds in clinical trials; antineoplastic drug discovery
22.  Drug discovery from natural sources 
The AAPS Journal  2006;8(2):E239-E253.
Organic compounds from terrestrial and marine organisms have extensive past and present use in the treatment of many diseases and serve as compounds of interest both in their natural form and as templates for synthetic modification. Over 20 new drugs launched on the market between 2000 and 2005, originating from terrestrial plants, terrestrial microorganisms, marine organisms, and terrestrial vertebrates and invertebrates, are described. These approved substances, representative of very wide chemical diversity, together with several other natural products or their analogs undergoing clinical trials, continue to demonstrate the importance of compounds from natural sources in modern drug discovery efforts.
PMCID: PMC3231566  PMID: 16796374
natural products; drug discovery; terrestrial plants; terrestrial microorganisms; marine organisms; terrestrial vertebrates; terrestrial invertebrates; chemical diversity
23.  Recent Advances in the Chemistry and Biology of Naturally Occurring Antibiotics 
Ever since the world-shaping discovery of penicillin, nature’s molecular diversity has been extensively screened for new medications and lead compounds in drug discovery. The search for anti-infective agents intended to combat infectious diseases has been of particular interest and has enjoyed a high degree of success. Indeed, the history of antibiotics is marked with impressive discoveries and drug development stories, the overwhelming majority of which have their origins in nature. Chemistry, and in particular chemical synthesis, has played a major role in bringing naturally occurring antibiotics and their derivatives to the clinic, and no doubt these disciplines will continue to be key enabling technologies for future developments in the field. In this review article, we highlight a number of recent discoveries and advances in the chemistry, biology, and medicine of naturally occurring antibiotics, with particular emphasis on the total synthesis, analog design, and biological evaluation of molecules with novel mechanisms of action.
PMCID: PMC2730216  PMID: 19130444
antibiotics; drugs; natural product; structure–property relationship; synthesis (org.)
24.  How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials? 
Malaria Journal  2011;10(Suppl 1):S2.
Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds.
PMCID: PMC3059460  PMID: 21411013
25.  Network based elucidation of drug response: from modulators to targets 
BMC Systems Biology  2013;7:139.
Network-based drug discovery aims at harnessing the power of networks to investigate the mechanism of action of existing drugs, or new molecules, in order to identify innovative therapeutic treatments. In this review, we describe some of the most recent advances in the field of network pharmacology, starting with approaches relying on computational models of transcriptional networks, then moving to protein and signaling network models and concluding with “drug networks”. These networks are derived from different sources of experimental data, or literature-based analysis, and provide a complementary view of drug mode of action. Molecular and drug networks are powerful integrated computational and experimental approaches that will likely speed up and improve the drug discovery process, once fully integrated into the academic and industrial drug discovery pipeline.
PMCID: PMC3878740  PMID: 24330611
Network pharmacology; Drug mode of action; Drug repositioning

Results 1-25 (1090036)