Current computational methods for predicting protein interactions of natural products

Moumbock, Aurélien F. A.; Li, Jianyu; Mishra, Pankaj; Gao, Mingjie; Günther, Stefan

doi:10.1016/j.csbj.2019.08.008

Cited by 45 publications

(35 citation statements)

References 144 publications

(147 reference statements)

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“…Amongst the reported HDAC inhibitors from nature are the macrocyclics; romidepsin and largazole, having a thiol ZBG in their activated forms [27] . In this regard, substructure searching, [24g] which represents a simple but powerful tool in drug discovery to perform initial filtration of molecules implemented in our online database was used to search for molecules with a thiol group, sulphur containing ZBG or sulphur‐containing molecules that can also be activated to HDAC inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Pharmacoinformatic Investigation of Medicinal Plants from East Africa

Simoben

Qaseem

Moumbock

et al. 2020

Molecular Informatics

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Medicinal plants have widely been used in the traditional treatment of ailments and have been proven effective. Their contribution still holds an important place in modern drug discovery due to their chemical, and biological diversities. However, the poor documentation of traditional medicine, in developing African countries for instance, can lead to the loss of knowledge related to such practices. In this study, we present the Eastern Africa Natural Products Database (EANPDB) containing the structural and bioactivity information of 1870 unique molecules isolated from about 300 source species from the Eastern African region. This represents the largest collection of natural products (NPs) from this geographical region, covering literature data of the period from 1962 to 2019. The computed physicochemical properties and toxicity profiles of each compound have been included. A comparative analysis of some physico‐chemical properties like molecular weight, H‐bond donor/acceptor, logPo/w, etc. as well scaffold diversity analysis has been carried out with other published NP databases. EANPDB was combined with the previously published Northern African Natural Products Database (NANPDB), to form a merger African Natural Products Database (ANPDB), containing ∼6500 unique molecules isolated from about 1000 source species (freely available at http://african‐compounds.org). As a case study, latrunculins A and B isolated from the sponge Negombata magnifica (Podospongiidae) with previously reported antitumour activities, were identified via substructure searching as molecules to be explored as putative binders of histone deacetylases (HDACs).

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Section: Methodsmentioning

confidence: 99%

Pharmacoinformatic Investigation of Medicinal Plants from East Africa

Simoben

Qaseem

Moumbock

et al. 2020

Molecular Informatics

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“…The off-target effect of a small molecule predicts not only the possible side effect but also the phenotypic outcome [163]. With the development of structural biology and computational methods, structures of targets and small molecules can be used to predict the off-target effect, providing a fast and economic way to evaluate the safety of the compounds [164].…”

Section: Characterization Of On-and Off-target Effectsmentioning

confidence: 99%

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

Kang

2020

IJMS

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Small-molecule drugs are organic compounds affecting molecular pathways by targeting important proteins. These compounds have a low molecular weight, making them penetrate cells easily. Small-molecule drugs can be developed from leads derived from rational drug design or isolated from natural resources. A target-based drug discovery project usually includes target identification, target validation, hit identification, hit to lead and lead optimization. Understanding molecular interactions between small molecules and their targets is critical in drug discovery. Although many biophysical and biochemical methods are able to elucidate molecular interactions of small molecules with their targets, structural biology is the most powerful tool to determine the mechanisms of action for both targets and the developed compounds. Herein, we reviewed the application of structural biology to investigate binding modes of orthosteric and allosteric inhibitors. It is exemplified that structural biology provides a clear view of the binding modes of protease inhibitors and phosphatase inhibitors. We also demonstrate that structural biology provides insights into the function of a target and identifies a druggable site for rational drug design.

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“…Compounds 1-3, 5, 7, and 12 were identified as the most potentially cytotoxic agents. We utilized cheminformatics techniques [51][52][53][54] to predict the most probable drug targets of these compounds. The kyoto encyclopedia of genes and genome (KEGG) database showed that seven major cancer drug targets are associated with triple-negative breast cancer including epidermal growth factor receptor (EGFR), proto-oncogene tyrosine-protein kinase Kit (c-KIT), insulin-like growth factor receptor 1 (IGFR1), notch receptor 1 (notch 1), phosphatidylinositol-3,4,5-trisphosphate-3-phosphatase (PTEN), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), and cyclin-dependent kinase 4 (CDK4).…”

Section: Human Intracellular Drug Targetsmentioning

confidence: 99%

Antiproliferative and Carbonic Anhydrase II Inhibitory Potential of Chemical Constituents from Lycium shawii and Aloe vera: Evidence from In Silico Target Fishing and In Vitro Testing

et al. 2020

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Lycium shawii Roem. & Schult and resin of Aloe vera (L.) BURM. F. are commonly used in Omani traditional medication against various ailments. Herein, their antiproliferative and antioxidant potential was explored. Bioassay-guided fractionation of the methanol extract of both plants led to the isolation of 14 known compounds, viz., 1–9 from L. shawii and 10–20 from A. vera. Their structures were confirmed by combined spectroscopic techniques including 1D (1H and 13C) and 2D (HMBC, HSQC, COSY) nuclear magnetic resonance (NMR), and electrospray ionization-mass spectrometry (ESI-MS). The cytotoxic potential of isolates was tested against the triple-negative breast cancer cell line (MDA-MB-231). Compound 5 exhibited excellent antiproliferative activity in a range of 31 μM, followed by compounds 1–3, 7, and 12, which depicted IC50 values in the range of 35–60 μM, while 8, 6, and 9 also demonstrated IC50 values >72 μM. Subsequently, in silico target fishing was applied to predict the most potential cellular drug targets of the active compounds, using pharmacophore modeling and inverse molecular docking approach. The extensive in silico analysis suggests that our compounds may target carbonic anhydrase II (CA-II) to exert their anticancer activities. When tested on CA-II, compounds 5 (IC50 = 14.4 µM), 12 (IC50 = 23.3), and 2 (IC50 = 24.4 µM) showed excellent biological activities in vitro. Additionally, the ethyl acetate fraction of both plants showed promising antioxidant activity. Among the isolated compounds, 4 possesses the highest antioxidant (55 μM) activity followed by 14 (241 μM). The results indicated that compound 4 can be a promising candidate for antioxidant drugs, while compound 5 is a potential candidate for anticancer drugs.

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Current computational methods for predicting protein interactions of natural products

Abstract: Graphical abstract

Cited by 45 publications

References 144 publications

Pharmacoinformatic Investigation of Medicinal Plants from East Africa

Pharmacoinformatic Investigation of Medicinal Plants from East Africa

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

Antiproliferative and Carbonic Anhydrase II Inhibitory Potential of Chemical Constituents from Lycium shawii and Aloe vera: Evidence from In Silico Target Fishing and In Vitro Testing

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