Discovery of a nanomolar glyoxalase-I inhibitor using integrated ligand-based pharmacophore modeling and molecular docking

Al-Shar’i, Nizar A.; Al-Rousan, Enas K.; Fakhouri, Lara; Al-Balas, Qosay; Hassan, Mohammad

doi:10.1007/s00044-019-02486-3

Cited by 15 publications

(7 citation statements)

References 39 publications

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“…The ligands exhibiting a LibDock score greater than 100 were filtered and were further analyzed using the CDOCKER (CHARMM-based DOCKER) protocol. The top-ranked poses with the most negative, favourable interactions were carried forward for further analysis [ 24 ]. Finally, the “Calculate Binding Energy” module of CDOCKER was used to calculate the binding energy of filtered poses.…”

Section: Methodsmentioning

confidence: 99%

Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach

Kumar

Krishna

Pradeep

et al. 2021

Computers in Biology and Medicine

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Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that has been spreading across the globe. The World Health Organization (WHO) declared it as a public health emergency. The treatment of COVID-19 has been hampered due to the lack of effective therapeutic efforts. Main Protease (M pro ) is a key enzyme in the viral replication cycle and its non-specificity to human protease makes it a potential drug target. Cyperus rotundus Linn, which belongs to the Cyperaceae family, is a traditional herbal medicine that has been widely studied for its antiviral properties. In this study, a computational approach was used to screen natural compounds from C. rotundus Linn using BIOVIA Discovery Suite and novel potential molecules against M pro of SARS-CoV-2 were predicted. Molecular docking was performed using LibDock protocol and selected ligands were further subjected to docking analysis by CDOCKER. The docking scores of the selected ligands were compared with standard antiretroviral drugs such as lopinavir and ritonavir to assess their binding potentials. Interaction pharmacophore analysis was then performed for the compounds exhibiting good binding scores to evaluate their protein–ligand interactions. The selected protein–ligand complexes were subjected to molecular dynamics simulation for 50 ns. Results of binding free energy analysis revealed that two compounds—β-amyrin and stigmasta-5,22-dien-3-ol—exhibited the best binding interactions and stability. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were performed to understand the pharmacokinetic properties and safety profile of the compounds. The overall results indicate that the phytochemicals from Cyperus rotundus Linn , namely β-amyrin and stigmasta-5,22-dien-3-ol, can be screened as potential inhibitors of SARS-CoV-2 M pro .

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Section: Methodsmentioning

confidence: 99%

Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach

Kumar

Krishna

Pradeep

et al. 2021

Computers in Biology and Medicine

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“…One of the promising drug targets, which have been the focus of our research group over the past decade, that can be of therapeutic potential is the glyoxalase system [3][4][5][6][7][8][9][10][11][12][13][14]. The glyoxalase system is a detoxifying pathway which converts reactive metabolic aldehydes, such as methylglyoxal, into nontoxic S-D-lactoyl-glutathione [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Potent Thiazolidinedione Salicylic Acid Inhibitors Against Glyoxalase-I as Potential Anticancer Agents

Alomari,

Fakhouri,

Al-Shar’i

et al. 2024

Preprint

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The worldwide rise in cancer incidence and mortality rates has spurred the search for new pathways implicated in cancer development and progression. One such target is glyoxalase 1 (GLO-I), a key player in methylglyoxal detoxification and a factor in the proliferation and prognosis of numerous cancers. Recent studies led by Al-Shar’i et al utilized computer-aided drug design to identify potential inhibitors of GLO-I. The second most potent hit, (Z)-5-(5-((2,4-dioxothiazolidin-5-ylidene)methyl)furan-2-yl)-2-hydroxybenzoic acid, (IC50 = 4.24 µM), was selected as a lead for further optimization. Through molecular docking, 27 analogues were designed and evaluated for binding affinity, with 14 of the top-scorings synthesized and tested for their inhibitory activity against GLO-I. The majority of these analogues showed enhanced activities relative to the lead compound, with the most potent having an IC50 of 150 nM. These findings pave the way for the continued development of highly effective GLO-I inhibitors.

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“…Because to these possible antiviral qualities, natural products and herbal treatments have attracted considerable interest in this situation. For instance, turmeric has been traditionally used to treat a number of diseases and possesses a broad spectrum of therapeutic properties, [6,7], including anti-diabetic [8], anti-tumor [9], platelet aggregation inhibition [10], antioxidant [11], anti-in ammatory [12], and Alzheimer's effects [13]. Moreover, unlike allopathic drugs, turmeric has no or minimal reported side effects, making it a viable natural alternative.…”

Section: Introductionmentioning

confidence: 99%

Herbal medicine (Curcuma longa) inspired volatile compounds as potential inhalants against SARS-CoV-2: An in-silico strategy and modeling study

Jayashankar

Punith

Swamy

et al. 2023

Preprint

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From the metabolite ecology (KNapSAcK) and herbs medicinal plants, phytochemistry, and therapeutics (IMPPAT) databases, the phytoconstituents from the herbal natural inhalant (turmeric) were taken. More samples of the phytoconstituents that adhere to drug likeness limits were obtained for in-silico research. To identify SARS-CoV-2 inhibitors, the Drug Likeness and ADMET experiments were used to screen volatile molecules from natural medicinal inhalants. The seven chemicals that make up turmeric all adhere to the ADMET restrictions and interact well with the Covid-19 proteins. Two active molecules are predicted by molecular docking studies to have strong binding affinity with the Sars-CoV-2 proteins (6LU7 and 6M0J). Based on this study 2 phytochemicals from turmeric, they have good binding affinity. DFT computing is applied to elucidate the molecular characteristics, and the molecular electrostatic potential (MEP) is generated to analyses the distribution of charges. These substances could be further subjected to in-vitro studies to evaluate their efficacy against Covid-19.

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Discovery of a nanomolar glyoxalase-I inhibitor using integrated ligand-based pharmacophore modeling and molecular docking

Cited by 15 publications

References 39 publications

Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach

Screening of natural compounds from Cyperus rotundus Linn against SARS-CoV-2 main protease (Mpro): An integrated computational approach

Design, Synthesis and Biological Evaluation of Potent Thiazolidinedione Salicylic Acid Inhibitors Against Glyoxalase-I as Potential Anticancer Agents

Herbal medicine (Curcuma longa) inspired volatile compounds as potential inhalants against SARS-CoV-2: An in-silico strategy and modeling study

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