Bisbenzylisoquinolines from Cissampelos pareira L. as antimalarial agents: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies

Suresh, P. K.; Kesarwani, Veerbhan; Kumari, Surekha; Shankar, Ravi; Sharma, Upendra

doi:10.1016/j.compbiolchem.2023.107826

Cited by 13 publications

(4 citation statements)

References 43 publications

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“…Using molecular mechanics‐generalized born surface area (MM‐GBSA) calculations to find the free binding energy is an excellent way to confirm the predicted potential affinity of a ligand for its protein target [28] . The more negative MM‐GBSA ΔG binding free energy values show greater binding free energy, indicating more efficient interaction and a more stable ligand‐receptor complex [29] . In this study, prime MM‐GBSA ΔG binding free energy values were computed to analyze the binding modes of the most active compounds ( 4 b , 4 c , and 4 e ) into the selected protein targets to determine the binding stability between ligand and receptor complexes of docked molecules through calculating the free binding energy.…”

Section: Resultsmentioning

confidence: 99%

“…[28] The more negative MM-GBSA ΔG binding free energy values show greater binding free energy, indicating more efficient interaction and a more stable ligand-receptor complex. [29] In this study, prime MM-GBSA ΔG binding free energy values were computed to analyze the binding modes of the most active compounds (4 b, 4 c, and 4 e) into the selected protein targets to determine the binding stability between ligand and receptor complexes of docked molecules through calculating the free binding energy. The IFD docking scores (kcal/mol) and MM-GBSA ΔG binding free energies were used to determine the binding properties and binding affinity of molecules.…”

Section: Molecular Docking Studies and Prime Mm-gbsa δG Binding Free ...mentioning

confidence: 99%

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Synthesis and Anticancer Activity of Novel Derivatives of α,β‐Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells

Şenol,

Ghaffari‐Moghaddam,

Bulut

et al. 2023

Chemistry & Biodiversity

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Herein, new derivatives of α,β‐unsaturated ketones based on oleanolic acid (4a‐i) were designed, synthesized, characterized, and tested against human prostate cancer (PC3). According to the in vitro cytotoxic study, title compounds (4a‐i) showed significantly lower toxicity toward healthy cells (HUVEC) in comparison with the reference drug doxorubicin. The compounds with the lowest IC50 values on PC3 cell lines were 4b (7.785 µM), 4c (8.869 µM), and 4e (8.765 µM). The results of the ADME calculations showed that the drug‐likeness parameters were within the defined ranges according to Lipinski’s and Jorgensen's rules. For the most potent compounds 4b, 4c, and 4e, a molecular docking analysis using the induced fit docking (IFD) protocol was performed against three protein targets (PARP, PI3K, and mTOR). Based on the IFD scores, compound 4b had the highest calculated affinity for PARP1, while compound 4c had higher affinities for mTOR and PI3K. The MM‐GBSA calculations showed that the most potent compounds had high binding affinities and formed stable complexes with the protein targets. Finally, a 50 ns molecular dynamics simulation was performed to study the behavior of protein target complexes under in silico physiological conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Docking Studies and Prime Mm-gbsa δG Binding Free ...mentioning

confidence: 99%

Synthesis and Anticancer Activity of Novel Derivatives of α,β‐Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells

Şenol,

Ghaffari‐Moghaddam,

Bulut

et al. 2023

Chemistry & Biodiversity

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“…[ 33 ] The more negative MM‐GBSA Δ G binding free energy values show greater binding free energy indicating more efficient interaction and more stable ligand–receptor complex. [ 34 ] In this study, prime MM‐GBSA Δ G binding free energy values were computed to analyze the binding modes of the most active compounds ( 4 , 5 , and 6 ) into the selected protein targets to determine the binding stability between ligand and receptor complexes of docked molecules through calculating the free binding energy. The IFD docking scores (kcal/mol) and MM‐GBSA Δ G binding free energies (kcal/mol) were used to determine the binding properties and binding affinity of molecules and they were given in Table 2.…”

Section: Resultsmentioning

confidence: 99%

Novel quinazoline–chromene hybrids as anticancer agents: Synthesis, biological activity, molecular docking, dynamics and ADME studies

Tokalı,

Şenol,

Yetke

et al. 2023

Archiv der Pharmazie

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In this study, new quinazoline–chromene hybrid compounds were synthesized. The cytotoxic effects on cell viability of the hybrid compounds were tested against A549 human lung adenocarcinoma and BEAS‐2B healthy bronchial epithelial cell lines in vitro. In addition, the ability of the active compounds to inhibit cell migration was tested. Molecular docking studies were performed to evaluate the ligand–protein interactions, and molecular dynamics simulations were performed to determine the interactions and stability of ligand–protein complexes. In silico absorption, distribution, metabolism, and excretion (ADME) studies were conducted to estimate the drug‐likeness of the compounds. Compounds 4 (IC50 = 51.2 µM) and 5 (IC50 = 44.2 µM) were found to be the most active agents against A549 cells. They are found to be more selective against A549 cells than the reference drug doxorubicin. They also have the ability to significantly inhibit cell migration. They have the best docking scores against epidermal growth factor receptor (EGFR) (−11.300 and −11.226 kcal/mol) and vascular endothelial growth factor receptor 2 (VEGFR2) (−10.987 and −11.247 kcal/mol), respectively. In MD simulations, compounds 4 and 5 have strong hydrogen bond interactions above 80% of simulation times and showed a low ligand root mean square deviation (RMSD) around 2 Å. According to the ADME analysis, compounds 4 and 5 exhibit excellent drug‐likeness and pharmacokinetic characteristics.

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“…falciparum 74 , Hayatinine and Curine have been reported to putatively bind Pfdihydrofolate reductase, PfcGMP-dependent protein kinase, and Pfprolyl-tRNA synthetase 75 .…”

Section: Discussionmentioning

confidence: 99%

Identification of novel, potent, and selective compounds against malaria using Glideosomal Associated Protein 50 as a drug Target

Agrawal¹,

Kumari

Mohammed³

et al. 2023

Preprint

Self Cite

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Phylum apicomplexan consists of parasites like Plasmodium and Toxoplasma. These obligate intracellular parasites enter host cells via an energy-dependent process using a specialized machinery called glideosome. In the present study, we used Plasmodium falciparum GAP 50, a glideosome-associated protein as a target to screen 951 different compounds from diverse chemical libraries. Using different screening methods, eight compounds, Hayatinine, Curine, MMV689758 (Bedaquiline), MMV1634402 (Brilacidin), and MMV688271, MMV782353, MMV642550, and USINB4-124-8 were identified which showed promising binding affinity (KD < 75 µM) along with sub-micromolar range anti-parasitic efficacy and selectivity index for malaria parasite > 100 fold. These eight compounds were effective against the chloroquine-resistant PfINDO and artemisinin-resistant, PfCam 3.1R359T strain. Studies on the effect of these compounds at asexual blood stages showed that these eight compounds act differently at different developmental stages, indicating the binding of these compounds to other Plasmodium proteins besides binding to PfGAP50. We further studied the effect of compounds in vivo P. berghei mouse model of malaria. Importantly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia, and three out of seven mice were cured of the infection. Thus, our study provides new scaffolds for the development of antimalarials that may act at multiple Plasmodium life cycle stages.

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Bisbenzylisoquinolines from Cissampelos pareira L. as antimalarial agents: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies

Cited by 13 publications

References 43 publications

Synthesis and Anticancer Activity of Novel Derivatives of α,β‐Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells

Synthesis and Anticancer Activity of Novel Derivatives of α,β‐Unsaturated Ketones Based on Oleanolic Acid: in Vitro and in Silico Studies against Prostate Cancer Cells

Novel quinazoline–chromene hybrids as anticancer agents: Synthesis, biological activity, molecular docking, dynamics and ADME studies

Identification of novel, potent, and selective compounds against malaria using Glideosomal Associated Protein 50 as a drug Target

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