Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

Yñigez-Gutierrez, Audrey E; Bachmann, Brian O.

doi:10.1021/acs.jmedchem.9b00246

Cited by 37 publications

(26 citation statements)

References 241 publications

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“…There are many examples: anticancer drugs such as docetaxel (Taxotere™), paclitaxel (Taxol™), vinblastine, podophyllotoxin (Condylin™), or etoposide; steroidal hormones such as progesterone, norgestrel, or cortisone; cardiac glycosides such as digitoxigenin; antibiotics like penicillin, streptomycin, and cephalosporins [see IA Ross for more examples (1999)]. Furthermore, Rodrigues et al (2016) pointed to the fact that fragments derived from natural structures are a source of diverse molecules from which new drugs can be designed, thanks to the fragment-based drug discovery approach (Erlanson et al, 2016;Mortenson et al, 2018;Yñigez-Gutierrez and Bachmann, 2019).…”

Section: Drugs and Natural Productsmentioning

confidence: 99%

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Lautie

Russo

Ducrot³

2020

Front. Pharmacol.

159

120

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The screening and testing of extracts against a variety of pharmacological targets in order to benefit from the immense natural chemical diversity is a concern in many laboratories worldwide. And several successes have been recorded in finding new actives in natural products, some of which have become new drugs or new sources of inspiration for drugs. But in view of the vast amount of research on the subject, it is surprising that not more drug candidates were found. In our view, it is fundamental to reflect upon the approaches of such drug discovery programs and the technical processes that are used, along with their inherent difficulties and biases. Based on an extensive survey of recent publications, we discuss the origin and the variety of natural chemical diversity as well as the strategies to having the potential to embrace this diversity. It seemed to us that some of the difficulties of the area could be related with the technical approaches that are used, so the present review begins with synthetizing some of the more used discovery strategies, exemplifying some key points, in order to address some of their limitations. It appears that one of the challenges of natural product-based drug discovery programs should be an easier access to renewable sources of plant-derived products. Maximizing the use of the data together with the exploration of chemical diversity while working on reasonable supply of natural product-based entities could be a way to answer this challenge. We suggested alternative ways to access and explore part of this chemical diversity with in vitro cultures. We also reinforced how important it was organizing and making available this worldwide knowledge in an "inventory" of natural products and their sources. And finally, we focused on strategies based on synthetic biology and syntheses that allow reaching industrial scale supply. Approaches based on the opportunities lying in untapped natural plant chemical diversity are also considered.

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Section: Drugs and Natural Productsmentioning

confidence: 99%

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Lautie

Russo

Ducrot³

2020

Front. Pharmacol.

159

120

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“…Advances in synthetic biology and organic synthesis methodology such as biosynthetic gene cluster manipulation, total synthesis, semisynthesis, or a combination of these methods have identified a new generation of natural product scaffolds that can be systematically targeted, to increase the activity, decrease the toxicity, and/or improve the physicochemical and pharmacokinetic properties [ 78 ]. This can also be applied as done in other natural leads during synthesis and lead optimization to improve the druglikeness of the compounds [ 79 , 80 ]. The synthetic accessibility score of the compounds ranged from 4.16 to 5.32.…”

Section: Resultsmentioning

confidence: 99%

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

Iheagwam

Rotimi

2020

Scientifica

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The COVID-19 pandemic, which started in Wuhan, China, has spread rapidly over the world with no known antiviral therapy or vaccine. Interestingly, traditional Chinese medicine helped in flattening the pandemic curve in China. In this study, molecules from African medicinal plants were analysed as potential candidates against multiple SARS-CoV-2 therapeutic targets. Sixty-five molecules from the ZINC database subset (AfroDb Natural Products) were virtually screened with some reported repurposed therapeutics against six SARS-CoV-2 and two human targets. Molecular docking, druglikeness, absorption, distribution, metabolism, excretion, and toxicity (ADMET) of the best hits were further simulated. Of the 65 compounds, only three, namely, 3-galloylcatechin, proanthocyanidin B1, and luteolin 7-galactoside found in almond (Terminalia catappa), grape (Vitis vinifera), and common verbena (Verbena officinalis), were able to bind to all eight targets better than the reported repurposed drugs. The findings suggest these molecules may play a role as therapeutic leads in tackling this pandemic due to their multitarget activity.

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“…[12][13][14][15] However, geldanamycin exhibits poor bioavailability and hepatotoxicity, 16 stimulating the pursuit of new analogues to address these issues via total 17,18 and semi-synthetic methods. [19][20][21][22] In fact, geldanamycin derivatives, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), 23 have reached clinical trials for the treatment of many types of cancer, including colorectal, breast, ovarian, lung, multiple myeloma, and leukemia. 24 In addition, geldanamycin is a challenge for confronting chemoselectivity, as it contains two alkenyl regions for epoxidationa diene and an isolated trisubstituted alkene, along with quinoid functionality replete with unsaturation.…”

Section: Introductionmentioning

confidence: 99%

Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

Hilton¹,

Brackett²,

Mercado³

et al. 2020

Preprint

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Catalytic, selective modifications of natural products can be a fertile platform for unveiling not only new natural product analogs with altered biological activity, but also for revealing new reactivity and selectivity hierarchies for embedded functional groups in complex environments. Motivated by these intersecting aims, we report site and stereoselective oxidation reactions of geldanamycin facilitated by aspartyl-peptide catalysts. Through the isolation and characterization of four new geldanamycin oxides, we discovered a synergistic effect between lead peptide-based catalysts and geldanamycin, resulting in an unexpected reaction pathway. Curiously, it seems unlikely that our discoveries would not have been possible absent the outer sphere interactions intrinsic to both the catalyst and the natural product. The result is a set of new “meta” catalytic reactions that deliver both unknown and previously incompletely characterized geldanamycin analogs. Enabled by the catalytic, site-selective epoxidation of geldanamycin, biological assays were carried out to document the bioactivities of the new compounds.<div><br></div>

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Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine

Cited by 37 publications

References 241 publications

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Unraveling Plant Natural Chemical Diversity for Drug Discovery Purposes

Computer-Aided Analysis of Multiple SARS-CoV-2 Therapeutic Targets: Identification of Potent Molecules from African Medicinal Plants

Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

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