scholarly journals QSAR-Based Virtual Screening of Natural Products Database for Identification of Potent Antimalarial Hits

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 459
Author(s):  
Letícia Tiburcio Ferreira ◽  
Joyce V. B. Borba ◽  
José Teófilo Moreira-Filho ◽  
Aline Rimoldi ◽  
Carolina Horta Andrade ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Low Income ◽  
In Silico ◽  
Biologically Active ◽  
Drug Resistant ◽  
Quantitative Structure ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

With about 400,000 annual deaths worldwide, malaria remains a public health burden in tropical and subtropical areas, especially in low-income countries. Selection of drug-resistant Plasmodium strains has driven the need to explore novel antimalarial compounds with diverse modes of action. In this context, biodiversity has been widely exploited as a resourceful channel of biologically active compounds, as exemplified by antimalarial drugs such as quinine and artemisinin, derived from natural products. Thus, combining a natural product library and quantitative structure–activity relationship (QSAR)-based virtual screening, we have prioritized genuine and derivative natural compounds with potential antimalarial activity prior to in vitro testing. Experimental validation against cultured chloroquine-sensitive and multi-drug-resistant P. falciparum strains confirmed the potent and selective activity of two sesquiterpene lactones (LDT-597 and LDT-598) identified in silico. Quantitative structure–property relationship (QSPR) models predicted absorption, distribution, metabolism, and excretion (ADME) and physiologically based pharmacokinetic (PBPK) parameters for the most promising compound, showing that it presents good physiologically based pharmacokinetic properties both in rats and humans. Altogether, the in vitro parasite growth inhibition results obtained from in silico screened compounds encourage the use of virtual screening campaigns for identification of promising natural compound-based antimalarial molecules.

Plasma concentration profiles for hepatotoxic pyrrolizidine alkaloid senkirkine in humans extrapolated from rat data sets using a simplified physiologically based pharmacokinetic model

2021 ◽  
Vol 15 ◽  
Author(s):  
Yusuke Kamiya ◽  
Tomonori Miura ◽  
Airi Kato ◽  
Norie Murayama ◽  
Makiko Shimizu ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Human Plasma ◽  
In Silico ◽  
Pbpk Model ◽  
Pyrrolizidine Alkaloid ◽  
Water Soluble ◽  
Food Plants ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Aim: The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

scholarly journals In Silico De Novo Curcuminoid Derivatives From the Compound Library of Natural Products Research Laboratories Inhibit COVID-19 3CLpro Activity

2020 ◽  
Vol 15 (9) ◽  
pp. 1934578X2095326
Author(s):  
Jai-Sing Yang ◽  
Jo-Hua Chiang ◽  
Shih‑Chang Tsai ◽  
Yuan-Man Hsu ◽  
Da-Tian Bau ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Binding Affinity ◽  
High Throughput ◽  
In Silico ◽  
De Novo ◽  
Compound Library ◽  
Therapeutic Success ◽  
High Throughput Virtual Screening

The coronavirus disease 2019 (COVID‐19) outbreak caused by the 2019 novel coronavirus (2019-nCOV) is becoming increasingly serious. In March 2019, the Food and Drug Administration (FDA) designated remdesivir for compassionate use to treat COVID-19. Thus, the development of novel antiviral agents, antibodies, and vaccines against COVID-19 is an urgent research subject. Many laboratories and research organizations are actively investing in the development of new compounds for COVID-19. Through in silico high-throughput virtual screening, we have recently identified compounds from the compound library of Natural Products Research Laboratories (NPRL) that can bind to COVID-19 3Lpro polyprotein and block COVID-19 3Lpro activity through in silico high-throughput virtual screening. Curcuminoid derivatives (including NPRL334, NPRL339, NPRL342, NPRL346, NPRL407, NPRL415, NPRL420, NPRL472, and NPRL473) display strong binding affinity to COVID-19 3Lpro polyprotein. The binding site of curcuminoid derivatives to COVID-19 3Lpro polyprotein is the same as that of the FDA-approved human immunodeficiency virus protease inhibitor (lopinavir) to COVID-19 3Lpro polyprotein. The binding affinity of curcuminoid derivatives to COVID-19 3Lpro is stronger than that of lopinavir and curcumin. Among curcuminoid derivatives, NPRL-334 revealed the strongest binding affinity to COVID-19 3Lpro polyprotein and is speculated to have an anti-COVID-19 effect. In vitro and in vivo ongoing experiments are currently underway to confirm the present findings. This study sheds light on the drug design for COVID-19 3Lpro polyprotein. Basing on lead compound development, we provide new insights on inhibiting COVID-19 attachment to cells, reducing COVID-19 infection rate and drug side effects, and increasing therapeutic success rate.

scholarly journals Discovery of Two Brominated Oxindole Alkaloids as Staphylococcal DNA Gyrase and Pyruvate Kinase Inhibitors via Inverse Virtual Screening

2020 ◽  
Vol 8 (2) ◽  
pp. 293 ◽  
Author(s):  
Ahmed M. Sayed ◽  
Hani A. Alhadrami ◽  
Seham S. El-Hawary ◽  
Rabab Mohammed ◽  
Hossam M. Hassan ◽  
...  
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Pyruvate Kinase ◽  
Inhibitory Activity ◽  
In Silico ◽  
Kinase Inhibitors ◽  
Enzyme Inhibitor ◽  
Dna Gyrase ◽  
Binding Mode

In the present study, a small marine-derived natural products library was assessed for antibacterial potential. Among 36 isolated compounds, a number of bis-indole derivatives exhibited growth-inhibitory activity towards Gram-positive strains (Bacillus subtilis and multidrug-resistant Staphylococcus aureus). 5- and 6-trisindoline (5-Tris and 6-Tris) were the most active derivatives (minimum inhibitory concentration, MIC, 4–8 µM) that were subsequently selected for anti-biofilm activity evaluation. Only 5-Tris was able to inhibit the staphylococcal biofilm formation starting at a 5 µM concentration. In order to investigate their possible molecular targets, both natural products were subjected to in silico inverse virtual screening. Among 20 target proteins, DNA gyrase and pyruvate kinase were the most likely to be involved in the observed antibacterial and anti-biofilm activities of both selected natural products. The in vitro validation and in silico binding mode studies revealed that 5-Tris could act as a dual enzyme inhibitor (IC50 11.4 ± 0.03 and 6.6 ± 0.05 µM, respectively), while 6-Tris was a low micromolar gyrase-B inhibitor (IC50 2.1 ± 0.08 µM), indicating that the bromine position plays a crucial role in the determination of the antibacterial lead compound inhibitory activity.

scholarly journals Identification of Broad-Spectrum MMP Inhibitors by Virtual Screening

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4553
Author(s):  
Aleix Gimeno ◽  
Doretta Cuffaro ◽  
Elisa Nuti ◽  
María José Ojeda-Montes ◽  
Raúl Beltrán-Debón ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Natural Products ◽  
Virtual Screening ◽  
Broad Spectrum ◽  
In Silico ◽  
Mmp Inhibitors ◽  
Bioactivity Assay ◽  
The Family ◽  
Skin Wrinkling

Matrix metalloproteinases (MMPs) are the family of proteases that are mainly responsible for degrading extracellular matrix (ECM) components. In the skin, the overexpression of MMPs as a result of ultraviolet radiation triggers an imbalance in the ECM turnover in a process called photoaging, which ultimately results in skin wrinkling and premature skin ageing. Therefore, the inhibition of different enzymes of the MMP family at a topical level could have positive implications for photoaging. Considering that the MMP catalytic region is mostly conserved across different enzymes of the MMP family, in this study we aimed to design a virtual screening (VS) workflow to identify broad-spectrum MMP inhibitors that can be used to delay the development of photoaging. Our in silico approach was validated in vitro with 20 VS hits from the Specs library that were not only structurally different from one another but also from known MMP inhibitors. In this bioactivity assay, 18 of the 20 compounds inhibit at least one of the assayed MMPs at 100 μM (with 5 of them showing around 50% inhibition in all the tested MMPs at this concentration). Finally, this VS was used to identify natural products that have the potential to act as broad-spectrum MMP inhibitors and be used as a treatment for photoaging.

Discovery of New AKT1 Inhibitors by Combination of In silico Structure Based Virtual Screening Approaches and Biological Evaluations

2019 ◽  
Author(s):  
Filip Fratev ◽  
Denisse A. Gutierrez ◽  
Renato J. Aguilera ◽  
suman sirimulla
Keyword(s):  
Virtual Screening ◽  
Success Rate ◽  
Protein Interactions ◽  
In Silico ◽  
Biological Data ◽  
In Vitro Binding ◽  
Vitro Binding ◽  
Screening Protocol ◽  
Screening Approaches

AKT1 is emerging as a useful target for treating cancer. Herein, we discovered a new set of ligands that inhibit the AKT1, as shown by in vitro binding and cell line studies, using a newly designed virtual screening protocol that combines structure-based pharmacophore and docking screens. Taking together with the biological data, the combination of structure based pharamcophore and docking methods demonstrated reasonable success rate in identifying new inhibitors (60-70%) proving the success of aforementioned approach. A detail analysis of the ligand-protein interactions was performed explaining observed activities.<br>

Design, Synthesis and In-Vitro Biological Activity of Some New 1,3-Thiazolidine-4-One Derivatives as Chemotherapeutic Agents Using Virtual Screening Strategies

2020 ◽  
Vol 16 ◽  
Author(s):  
Pragya Nayak ◽  
Monica Kachroo
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virtual Screening ◽  
In Silico ◽  
Cancer Cell Line ◽  
Inhibitory Response ◽  
Chemotherapeutic Agents ◽  
Acceptor Site ◽  
Hydrogen Bond Acceptor ◽  
Screening Strategies

: A series of new heteroaryl thiazolidine-4-one derivatives were designed and subjected to in-silico prioritization using various virtual screening strategies. Two series of thiazolidinone derivatives were synthesized and screened for their in-vitro antitubercular, anticancer, antileishmanial and antibacterial (Staphylococcus aureus; Streptococcus pneumonia; Escherichia coli; Pseudomonas aeruginosa) activities. The compounds with electronegative substitutions exhibited positive antitubercular activity, the derivatives possessing a methyl substitution exhibited good inhibitory response against breast cancer cell line MCF-7 while the compounds possessing a hydrogen bond acceptor site like hydroxyl and methoxy substitution in their structures exhibited good in-vitro antileishmanial activity. Some compounds exhibited potent activity against gram positive bacteria Pseudomonas aeruginosa as compared to the standards. Altogether, the designed compounds exhibited good in-vitro anti-infective potential which was in good agreement with the in-silico predictions and they can be developed as important lead molecules for anti-infective and chemotherapeutic drug research.

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