Natural Products of Dietary Origin as Lead Compounds in Virtual Screening and Drug Design

: As per the1st of September 2020, the COVID-19 pandemic has reached an unprecedented level of more than 25 million cases with more than 850,000 deaths. Moreover, all the drug candidates are still undergoing testing in clinical trial. In this regard, a breakthrough in drug design is necessary. One strategy to devise lead compounds is leveraging natural products as a lead source. Several companies and research institutes are currently developing anti-SARS-CoV-2 leads from natural products. Flavanoids are well known as a class of antiviral compounds library. The objective of this research is to employ virtual screening methods for obtaining the best lead compounds from the library of flavonoid compounds. This research employed virtual screening methods that comprised of downloading the protein and lead compound structures, QSAR analysis prediction, iterations of molecular docking simulation, and ADME-TOX simulation for toxicity prediction. The QSAR analysis found that the tested compounds have broad-spectrum antiviral activity, and some of them exhibit specific binding to the 3C-like Protease of the Coronavirus. Moreover, juglanin was found as the compound with the most fit binding with the Protease enzyme of SARS-CoV-2. Although most of the tested compounds are deemed toxic by the ADME-Tox test, further research should be conducted to comprehend the most feasible strategy to deliver the drug to the infected lung cells. The juglanin compound is selected as the most fit candidate as the SARS-CoV-2 lead compound in the tested flavonoid samples. However, further research should be conducted to observe the lead delivery method to the cell.

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Design of Novel Bioisosteres of β-Diketo Acid Inhibitors of HIV-1 Integrase

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632020501600105 ◽

2005 ◽

Vol 16 (1) ◽

pp. 41-61 ◽

Cited By ~ 41

Author(s):

Mario Sechi ◽

Luciano Sannia ◽

Fabrizio Carta ◽

Michele Palomba ◽

Roberto Dallocchio ◽

...

Keyword(s):

Virtual Screening ◽

Drug Design ◽

Carboxylic Acids ◽

Active Site ◽

Docking Studies ◽

Design Strategies ◽

Structure Based Drug Design ◽

Computational Docking ◽

Lead Compounds ◽

Hiv 1

HIV-1 integrase (IN) is an attractive and validated target for the development of novel therapeutics against AIDS. Significant efforts have been devoted to the identification of IN inhibitors using various methods. In this context, through virtual screening of the NCI database and structure-based drug design strategies, we identified several pharmacophoric fragments and incorporated them on various aromatic or heteroaromatic rings. In addition, we designed and synthesized a series of 5-aryl(heteroaryl)-isoxazole-3-carboxylic acids as biological isosteric analogues of β-diketo acid containing inhibitors of HIV-1 IN and their derivatives. Further computational docking studies were performed to investigate the mode of interactions of the most active ligands with the IN active site. Results suggested that some of the tested compounds could be considered as lead compounds and suitable for further optimization.

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Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Potential Natural Products Based PDE1B Inhibitor Lead Compounds

Central Nervous System Agents in Medicinal Chemistry ◽

10.2174/1871524922666211231115638 ◽

2021 ◽

Vol 22 ◽

Author(s):

Teng Woei Shy ◽

Anand Gaurav

Keyword(s):

Natural Products ◽

Virtual Screening ◽

Natural Product ◽

Neuropsychiatric Disorders ◽

Major Health ◽

Pharmacophore Modelling ◽

Lead Compounds ◽

Medical Need ◽

Total Brain ◽

Pharmacophore Models

Aim: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders. Background: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders. Objectives: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database. Methods: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound. Results: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone. Conclusion: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.

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Combined strategies in structure-based virtual screening

Physical Chemistry Chemical Physics ◽

10.1039/c9cp06303j ◽

2020 ◽

Vol 22 (6) ◽

pp. 3149-3159 ◽

Cited By ~ 13

Author(s):

Zhe Wang ◽

Huiyong Sun ◽

Chao Shen ◽

Xueping Hu ◽

Junbo Gao ◽

...

Keyword(s):

Virtual Screening ◽

Drug Design ◽

Lead Compounds

The identification and optimization of lead compounds are inalienable components in drug design and discovery pipelines.

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Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone A

10.26434/chemrxiv.6103607.v1 ◽

2018 ◽

Author(s):

Jonathan J. Mills ◽

Kaylib R. Robinson ◽

Troy E. Zehnder ◽

Joshua G. Pierce

Keyword(s):

Natural Products ◽

Natural Product ◽

Mechanism Of Action ◽

Marine Natural Products ◽

Biological Evaluation ◽

Lead Compounds ◽

Follow Up Studies ◽

Initial Resistance ◽

Synthesis And Biological Evaluation

The lipoxazolidinone family of marine natural products, with an unusual 4-oxazolidinone heterocycle at their core, represents a new scaffold for antimicrobial discovery; however, questions regarding their mechanism of action and high lipophilicity have likely slowed follow-up studies. Herein, we report the first synthesis of lipoxazolidinone A, 15 structural analogs to explore its active pharmacophore, and initial resistance and mechanism of action studies. These results suggest that 4-oxazolidinones are valuable scaffolds for antimicrobial development and reveal simplified lead compounds for further optimization.

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Combinatorial Synthesis of Novel 9R-Acyloxyquinine Derivatives as Insecticidal Agents

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200120112714 ◽

2020 ◽

Vol 23 (2) ◽

pp. 111-118

Author(s):

Zhiping Che ◽

Jinming Yang ◽

Di Sun ◽

Yuee Tian ◽

Shengming Liu ◽

...

Keyword(s):

Natural Products ◽

Double Bond ◽

Insecticidal Activity ◽

Structural Modification ◽

Combinatorial Synthesis ◽

Hydroxyl Group ◽

Botanical Insecticide ◽

Mythimna Separata ◽

Lead Compounds

Background: It is one of the effective ways for pesticide innovation to develop new insecticides from natural products as lead compounds. Quinine, the main alkaloid in the bark of cinchona tree as well as in plants in the same genus, is recognized as a safe and potent botanical insecticide to many insects. The structural modification of quinine into 9R-acyloxyquinine derivatives is a potential approach for the development of novel insecticides, which showed more toxicity than quinine. However, there are no reports on the insecticidal activity of 9Racyloxyquinine derivatives to control Mythimna separata. Methods: Endeavor to discover biorational natural products-based insecticides, 20 novel 9Racyloxyquinine derivatives were prepared and assessed for their insecticidal activity against M. separata in vivo by the leaf-dipping method at 1 mg/mL. Results: Among all the compounds, especially derivatives 5i, 5k and 5t exhibited the best insecticidal activity with final mortality rates of 50.0%, 57.1%, and 53.6%, respectively. Conclusion: Overall, a free 9-hydroxyl group is not a prerequisite for insecticidal activity and C9- substitution is well tolerated; modification of out-ring double-bond is acceptable, and hydrogenation of double-bond enhances insecticidal activity; Quinine ring is essential and open of it is not acceptable. These preliminary results will pave the way for further modification of quinine in the development of potential new insecticides.

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Virtual Screening for Novel Staphylococcus Aureus NorA Efflux Pump Inhibitors From Natural Products

Medicinal Chemistry ◽

10.2174/1573406410666140902110903 ◽

2015 ◽

Vol 11 (2) ◽

pp. 135-155 ◽

Cited By ~ 17

Author(s):

Khac-Minh Thai ◽

Trieu-Du Ngo ◽

Thien-Vy Phan ◽

Thanh-Dao Tran ◽

Ngoc-Vinh Nguyen ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Natural Products ◽

Virtual Screening ◽

Efflux Pump ◽

Efflux Pump Inhibitors

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Structure-Based Designing, Solvent Less Synthesis of 1,2,3,4-Tetrahydropyrimidine-5-carboxylate Derivatives: A Combined In Vitro and In Silico Screening Approach

Molecules ◽

10.3390/molecules26154424 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4424

Author(s):

Uzma Arshad ◽

Sibtain Ahmed ◽

Nusrat Shafiq ◽

Zaheer Ahmad ◽

Aqsa Hassan ◽

...

Keyword(s):

Virtual Screening ◽

Catalytic Amount ◽

Pyrimidine Derivatives ◽

Qsar Studies ◽

Lead Compounds ◽

Biological Potential ◽

Anti Cancer ◽

Anti Oxidant ◽

Vitro Analysis

Objective: In this study, small molecules possessing tetrahydropyrimidine derivatives have been synthesized having halogenated benzyl derivatives and carboxylate linkage. As previously reported, FDA approved halogenated pyrimidine derivatives prompted us to synthesize novel compounds in order to evaluate their biological potential. Methodology: Eight pyrimidine derivatives have been synthesized from ethyl acetoacetate, secondary amine, aromatic benzaldehyde by adding catalytic amount of CuCl2·2H2O via solvent less Grindstone multicomponent reagent method. Molecular structure reactivity and virtual screening were performed to check their biological efficacy as an anti-oxidant, anti-cancer and anti-diabetic agent. These studies were supported by in vitro analysis and QSAR studies. Results: After combined experimental and virtual screening 5c, 5g and 5e could serve as lead compounds, having low IC50 and high binding affinity.

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Biosynthetic pathways and enzymes involved in the production of phosphonic acid natural products

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbaa052 ◽

2021 ◽

Vol 85 (1) ◽

pp. 42-52

Author(s):

Taro Shiraishi ◽

Tomohisa Kuzuyama

Keyword(s):

Natural Products ◽

Biosynthetic Pathway ◽

Organophosphorus Compounds ◽

Genome Mining ◽

Biological Molecules ◽

Antibacterial Drug ◽

Gene Encoding ◽

Quarter Century ◽

Lead Compounds ◽

Biosynthetic Machinery

Abstract Phosphonates are organophosphorus compounds possessing a characteristic C−P bond in which phosphorus is directly bonded to carbon. As phosphonates mimic the phosphates and carboxylates of biological molecules to potentially inhibit metabolic enzymes, they could be lead compounds for the development of a variety of drugs. Fosfomycin (FM) is a representative phosphonate natural product that is widely used as an antibacterial drug. Here, we review the biosynthesis of FM, which includes a recent breakthrough to find a missing link in the biosynthetic pathway that had been a mystery for a quarter-century. In addition, we describe the genome mining of phosphonate natural products using the biosynthetic gene encoding an enzyme that catalyzes C–P bond formation. We also introduce the chemoenzymatic synthesis of phosphonate derivatives. These studies expand the repertoires of phosphonates and the related biosynthetic machinery. This review mainly covers the years 2012-2020.

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