Investigation of indirubin derivatives: a combination of 3D-QSAR, molecular docking, and ADMET towards the design of new DRAK2 inhibitors

Aouidate, Adnane; Ghaleb, Adib; Ghamali, Mounir; Chtita, Samir; Ousaa, Abdellah; Choukrad, M’barek; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

doi:10.1007/s11224-018-1134-0

Cited by 16 publications

(12 citation statements)

References 31 publications

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“…In the rest of our work, to develop new antibacterial candidates based on the newly synthesized pyrazolic derivatives, we use structure 5c as a reference in the investigation of the properties of this structure based on the 3D-QSAR approach. 40,41 The 3D-QSAR studies were carried out on the 14 new pyrazole derivatives that are evaluated in vitro for their antibacterial activity against the E. coli bacterial strain (Tables 2 and 3). The aim of this study is to identify the molecular properties that influence the antibacterial activity of the pyrazole derivatives, and to design new pyrazoles with improved antibacterial activity.…”

Section: Resultsmentioning

confidence: 99%

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Design, synthesis, characterization,in vitroscreening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents

et al. 2022

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Section: Resultsmentioning

confidence: 99%

“…The developed 3D QSAR models in this work and the obtained contour maps were adapted for the structure of pyrazole derivatives using the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA) approaches. 40,41…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, characterization,in vitroscreening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents

et al. 2022

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“…Second, due to the essential role of GSK-3β in the development of various cancer types 3 , 7 , cytotoxic and selectivity of the derivatives were also evaluated in vitro against four human tumor cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal embryonic kidney cell line (HEK-293). Third, as indirubin and its derivatives are potential GSK-3β inhibitors 14 , 15 , molecular docking of studied compounds on GSK-3β enzyme were performed to explore the possible interaction within its active site. Fourth, the fast pulling of ligand (FPL) simulation was conducted to refine the binding affinity and mechanism of the ligand (molecule) to GSK-3β.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, to discover compounds with high biological activity for drug development, virtual screening has been considered as a convenient and economically efficient method. Previous investigations involving GSK-3β inhibitors have produced promising results in pharmacophore design 12,13 , docking 12,14,15 , and elaboration of structure-activity relationships 15,16 . However, the targeting behavior of GSK-3β toward indirubin, indirubin-3′oxime and its derivatives has not been clearly substantiated.…”

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confidence: 99%

Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

Dan

Quang

Truong

et al. 2020

Sci Rep

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The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields. Structures of new derivatives were also elucidated through 1D, 2D-NMR and HR-MS(eSi) spectra and X-ray crystallography. All designed compounds were screened for cytotoxic activity against four human cancer cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal kidney cell line (HEK-293). Compound 6f exhibited the most marked cytotoxicity meanwhile cytotoxicity of compounds 6e, 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. The fast pulling of ligand scheme was then employed to refine the binding affinity and mechanism between ligands and GSK-3β enzyme. the computational results are expected to contribute to predicting enzyme target of the trial inhibitors and their possible interaction, from which the design of new cytotoxic agents could be created in the future. Cancer is ranked second globally as cause of death. The disease originated due to the inability of cells to control growth, often leading to the formation of cancerous tumors or liquid cancer. (i.e. leukemia and lymphoma cancer). Routines for cancer treatment consist of chemotherapy and radiotherapy where the former utilizes molecule-size drugs aiming at eradication and inhibition of cancer tumors. However, this treatment technique has been shown to suffer from several inherent shortcomings including the development of drug resistance, off-target toxicity and limited targeting capabilities 1,2. Glycogen synthase kinase-3 (GSK-3) is defined as a multifunctional serine/threonine protein kinase that regulates the phosphorylation of various cellular targets 3. The function of GSK-3 is essential for the development

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“…Lipinski’s rule (with MW ≤ 500 g/mol, Log P ≤ 5, NR ≤ 10, HBA ≤ 10, HBD ≤ 5, PSA ≤ 140) has been applied to evaluate the molecules drug likeness [ 37 ]. Candidate violating no more than one of these criteria is likely to be developed as a prospective oral drug [ 38 ].…”

Section: Methodsmentioning

confidence: 99%

QSAR study of unsymmetrical aromatic disulfides as potent avian SARS-CoV main protease inhibitors using quantum chemical descriptors and statistical methods

Chtita

Belhassan

Bakhouch

et al. 2021

Chemometrics and Intelligent Laboratory Systems

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In silico research was executed on forty unsymmetrical aromatic disulfide derivatives as inhibitors of the SARS Coronavirus (SARS-CoV-1). Density functional theory (DFT) calculation with B3LYP functional employing 6-311+G(d,p) basis set was used to calculate quantum chemical descriptors. Topological, physicochemical and thermodynamic parameters were calculated using ChemOffice software. The dataset was divided randomly into training and test sets consisting of 32 and 8 compounds, respectively. In attempt to explore the structural requirements for bioactives molecules with significant anti-SARS-CoV-2 activity, we have built valid and robust statistics models using QSAR approach. Hundred linear pentavariate and quadrivariate models were established by changing training set compounds and further applied in test set to calculate predicted IC 50 values of compounds. Both built models were individually validated internally as well as externally along with Y-Randomization according to the OECD principles for the validation of QSAR model and the model acceptance criteria of Golbraikh and Tropsha’s. Model 34 is chosen with higher values of R 2 , R 2 test and Q 2 cv (R 2 = 0.838, R 2 test = 0.735, Q 2 cv = 0.757). It is very important to notice that anti-SARS-CoV main protease of these compounds appear to be mainly governed by five descriptors, i.e. highest occupied molecular orbital energy (E HOMO ), energy of molecular orbital below HOMO energy (E HOMO-1 ), Balaban index (BI), bond length between the two sulfur atoms (S1S2) and bond length between sulfur atom and benzene ring (S2Bnz). Here the possible action mechanism of these compounds was analyzed and discussed, in particular, important structural requirements for great SARS-CoV main protease inhibitor will be by substituting disulfides with smaller size electron withdrawing groups. Based on the best proposed QSAR model, some new compounds with higher SARS-CoV inhibitors activities have been designed. Further, in silico prediction studies on ADMET pharmacokinetics properties were conducted.

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Investigation of indirubin derivatives: a combination of 3D-QSAR, molecular docking, and ADMET towards the design of new DRAK2 inhibitors

Cited by 16 publications

References 31 publications

Design, synthesis, characterization,in vitroscreening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents

Design, synthesis, characterization,in vitroscreening, molecular docking, 3D-QSAR, and ADME-Tox investigations of novel pyrazole derivatives as antimicrobial agents

Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3β of new indirubin-3ʹ-oxime derivatives

QSAR study of unsymmetrical aromatic disulfides as potent avian SARS-CoV main protease inhibitors using quantum chemical descriptors and statistical methods

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