Role of Natural Products in Drug Discovery

Lachance, Hugo; Wetzel, Stefan; Waldmann, Herbert

doi:10.1002/9780470584170.ch7

Cited by 6 publications

(6 citation statements)

References 200 publications

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“…Despite this though, interest in natural product drug development waned at the end of the last century, owing to the technical difficulties of screening natural product extracts and the rise of combinatorial chemistry (combichem). In the intervening period, many new synthetic chemotypes were discovered and applied to drugs, through combichem did not fully live up to the heightened expectations and with accompanying technological advances in HTS, there is a renewed interest in natural products. − However, the supply from their natural sources is often unsustainable, and notwithstanding some impressive total synthesis efforts, − the chemical complexity of natural products frequently prohibits chemical access to sufficient quantities for advanced biological testing. Nevertheless, their unrivaled structural complexity, diversity, and biological relevance means that natural products will continue to provide a rich source of lead structures and important guiding principles for the design of compound libraries for screening campaigns.…”

Section: Approaches For Hit Identification Of Ppi Modulatorsmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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Direct interactions between proteins are essential for the regulation of their functions in biological pathways. Targeting the complex network of protein−protein interactions (PPIs) has now been widely recognized as an attractive means to therapeutically intervene in disease states. Even though this is a challenging endeavor and PPIs have long been regarded as "undruggable" targets, the last two decades have seen an increasing number of successful examples of PPI modulators, resulting in growing interest in this field. PPI modulation requires novel approaches and the integrated efforts of multiple disciplines to be a fruitful strategy. This perspective focuses on the hub-protein 14-3-3, which has several hundred identified protein interaction partners, and is therefore involved in a wide range of cellular processes and diseases. Here, we aim to provide an integrated overview of the approaches explored for the modulation of 14-3-3 PPIs and review the examples resulting from these efforts in both inhibiting and stabilizing specific 14-3-3 protein complexes by small molecules, peptide mimetics, and natural products.

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Section: Approaches For Hit Identification Of Ppi Modulatorsmentioning

confidence: 99%

Modulators of Protein–Protein Interactions

et al. 2014

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“…Historically, natural products have been known to be critical resources for drug discoveries to treat numerous diseases, including infectious diseases [9] . They are characterized by comprising an enormous diversity of scaffolds as well as by their structural complexity, serving as a reservoir of drug candidates.…”

Section: Introductionmentioning

confidence: 99%

Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular docking-based virtual screening with bio-layer interferometry

Zhang

Hamdoun

Chen

et al. 2021

Pharmacological Research

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Coronavirus Disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which enter the host cells through the interaction between its receptor binding domain (RBD) of spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) receptor on the plasma membrane of host cell. Neutralizing antibodies and peptide binders of RBD can block viral infection, however, the concern of accessibility and affordability of viral infection inhibitors has been raised. Here, we report the identification of natural compounds as potential SARS-CoV-2 entry inhibitors using the molecular docking-based virtual screening coupled with bilayer interferometry (BLI). From a library of 1871 natural compounds, epigallocatechin gallate (EGCG), 20(R)-ginsenoside Rg3 (RRg3), 20(S)-ginsenoside Rg3 (SRg3), isobavachalcone (Ibvc), isochlorogenic A (IscA) and bakuchiol (Bkc) effectively inhibited pseudovirus entry at concentrations up to 100 μM. Among these compounds, four compounds, EGCG, Ibvc, salvianolic acid A (SalA), and isoliensinine (Isl), were effective in inhibiting SARS-CoV-2-induced cytopathic effect and plaque formation in Vero E6 cells. The EGCG was further validated with no observable animal toxicity and certain antiviral effect against SARS-CoV-2 pseudovirus mutants (D614G, N501Y, N439K & Y453F). Interestingly, EGCG, Bkc and Ibvc bind to ACE2 receptor in BLI assay, suggesting a dual binding to RBD and ACE2. Current findings shed some insight into identifications and validations of SARS-CoV-2 entry inhibitors from natural compounds.

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“…Moreover, WHO list of essential drugs consists of 252 drugs, of which 11% are of plant origin. [10][11][12][13][14][15][16][17][18][19][20][21][22] Proper screening of biologically active natural products results in the identification of various bioactive molecules as well as drugs. [23][24][25][26][27][28][29][30] One such example is the discovery of the first analgesic, anti-inflammatory drug aspirin from the bark of willow tree by Greeks and Romans since 400 BC.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Molecular Modelling, and Biological Evaluation of Oleanolic Acid-Arylidene Derivatives as Potential Anti-Inflammatory Agents

Mir¹,

Godavari²,

Siddiqui³

et al. 2021

DDDT

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Introduction Oleanolic acid, a pentacyclic triterpenic acid, is widely distributed in medicinal plants and is the most commonly studied triterpene for various biological activities, including anti-allergic, anti-cancer, and anti-inflammatory. Methods The present study was carried out to synthesize arylidene derivatives of oleanolic acid at the C-2 position by Claisen Schmidt condensation to develop more effective anti-inflammatory agents. The derivatives were screened for anti-inflammatory activity by scrutinizing NO production inhibition in RAW 264.7 cells induced by LPS and their cytotoxicity. The potential candidates were further screened for inhibition of LPS-induced interleukin (IL-6) and tumour necrosis factor-alpha (TNF-α) production in RAW 264.7 cells. Results The results of in vitro studies revealed that derivatives 3d, 3e, 3L, and 3o are comparable to that of the oleanolic acid on the inhibition of TNF-α and IL-6 release. However, derivative 3L was identiﬁed as the most potent inhibitor of IL-6 (77.2%) and TNF-α (75.4%) when compared to parent compound, and compounds 3a (77.18%), 3d (71.5%), and 3e (68.8%) showed potent inhibition of NO than oleanolic acid (65.22%) at 10µM. Besides, from docking score and Cyscore analysis analogs (3e, 3L, 3n) showed greater affinity towards TNF-α and IL-1β than dexamethasone. Conclusion Herein, we report a series of 15 new arylidene derivatives of oleanolic acid by Claisen Schmidt condensation reaction. All the compounds synthesized were screened for their anti-inﬂammatory activity against NO, TNF-α and IL-6. From the data, it was evident that most of the compounds exhibited better anti-inﬂammatory activity.

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Role of Natural Products in Drug Discovery

Cited by 6 publications

References 200 publications

Modulators of Protein–Protein Interactions

Modulators of Protein–Protein Interactions

Identification of natural compounds as SARS-CoV-2 entry inhibitors by molecular docking-based virtual screening with bio-layer interferometry

Design, Synthesis, Molecular Modelling, and Biological Evaluation of Oleanolic Acid-Arylidene Derivatives as Potential Anti-Inflammatory Agents

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