Insights into the EGFR SAR of N-phenylquinazolin-4-amine-derivatives using quantum mechanical pairwise-interaction energies

Simeon, Saw; Jongkon, Nathjanan; Chotpatiwetchkul, Warot; Gleeson, M. Paul

doi:10.1007/s10822-019-00221-z

Cited by 6 publications

(5 citation statements)

References 89 publications

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“…In this 3D-QSAR study, the partial least squares (PLS) method was used to analyze the CoMFA and CoMSIA models, pIC 50 as the dependent variable, CoMFA and CoMSIA as the independent variables, to analyze the linear relationship between the structure of the compound and the biological activity values. 29 The cross-validation analysis was performed using the leave-one-out (LOO) method to obtain the cross-validation correlation coefficient ( q 2 ) and the best principal components ( N ). 30 The cross-validation coefficient q 2 can be calculated by the following formula: 31 where Y exp denotes the experimental value of the compound, Y pred denotes the predicted value of the compound, and Y mean denotes the average of the actual pIC 50 values for each compound.…”

Section: Methodsmentioning

confidence: 99%

Molecular docking, 3D-QASR and molecular dynamics simulations of benzimidazole Pin1 inhibitors

Liu,

Wang,

Liu

et al. 2024

Phys. Chem. Chem. Phys.

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Section: Methodsmentioning

confidence: 99%

Molecular docking, 3D-QASR and molecular dynamics simulations of benzimidazole Pin1 inhibitors

Liu,

Wang,

Liu

et al. 2024

Phys. Chem. Chem. Phys.

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“…The size of a grid box was 40 × 40 × 40 Å with the dimensions of 0.375 Å grid spacing. The GOLD docking protocol [ 86 ], as previously described, was carried out by using the empirical GoldScore [ 57 ] and ChemPLP [ 59 ] scoring fitness functions. These two scores of the best-docked pose were examined and compared with the binding energy computed by using AutoDock.…”

Section: Methodsmentioning

confidence: 99%

Computational Analysis and Biological Activities of Oxyresveratrol Analogues, the Putative Cyclooxygenase-2 Inhibitors

et al. 2022

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Polyphenols are a large family of naturally occurring phytochemicals. Herein, oxyresveratrol was isolated from ethanolic crude extracts of Artocarpus lacucha Buch.-Ham., and chemically modified to derive its lipophilic analogues. Biological screening assays showed their inhibitory potency against cyclooxygenase-2 (COX-2) with very low cytotoxicity to the MRC-5 normal cell lines. At the catalytic site of COX-2, docking protocols with ChemPLP, GoldScore and AutoDock scoring functions were carried out to reveal hydrogen bonding interactions with key polar contacts and hydrophobic pi-interactions. For more accurate binding energetics, COX-2/ligand complexes at the binding region were computed in vacuo and implicit aqueous solvation using M06-2X density functional with 6-31G+(d,p) basis set. Our computational results confirmed that dihydrooxyresveratrol (4) is the putative inhibitor of human COX-2 with the highest inhibitory activity (IC50 of 11.50 ± 1.54 µM) among studied non-fluorinated analogues for further lead optimization. Selective substitution of fluorine provides a stronger binding affinity; however, lowering the cytotoxicity of a fluorinated analogue to a normal cell is challenging. The consensus among biological activities, ChemPLP docking score and the binding energies computed at the quantum mechanical level is obviously helpful for identification of oxyresveratrol analogues as a putative anti-inflammatory agent.

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“…Therefore, it seeks latent variabels that have high variance and high correlation with the dependent variable by simultaneously projecting the descriptors into latent component to correlate with bioactivity values. PLS models have been commonly used to predict the ADMET properties 27 and in vitro potency of protein-ligand binding affinities 28 .…”

Section: Methodsmentioning

confidence: 99%

Characterizing the relationship between the chemical structures of drugs and their activities on primary cultures of pediatric solid tumors

Simeon

Ghislat

Ballester

2020

Preprint

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Better drugs are required to manage pediatric cancers. A high-throughput screen of drugs in primary cultures derived from orthotopic patient-derived xenografts (O-PDX) of pediatric solid tumours has been recently published. Here we analyzed these data sets to find out whether it is possible to leverage them for identifying new drug leads in a phenotypic manner. We found that drugs bearing a higher number of heterocyclic rings, two carbon-hetero bonds and halogens are associated to submicromolar potency in alveolar rhabdomyosarcoma and osteosarcoma O-PDXs. Furthermore, Murcko scaffolds 1-cyclopentyl-octahydro-1H-indene and tetradecahydroanthracene can be utilized as starting scaffolds to selectively optimize potency against osteosarcoma since drugs bearing this scaffold displayed superior O-PDX culture potency. Lastly, we have generated QSAR (Quantitative Structure-Activity Relationship) models able to predict the potency of drugs on each O-PDX tumor. To permit their use to guide drug repositioning on these 30 O-PDX cell cultures, we are providing a user-friendly web server implementing these QSAR models at https://rnewbie.shinyapps.io/Shobek-master

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Insights into the EGFR SAR of N-phenylquinazolin-4-amine-derivatives using quantum mechanical pairwise-interaction energies

Cited by 6 publications

References 89 publications

Molecular docking, 3D-QASR and molecular dynamics simulations of benzimidazole Pin1 inhibitors

Molecular docking, 3D-QASR and molecular dynamics simulations of benzimidazole Pin1 inhibitors

Computational Analysis and Biological Activities of Oxyresveratrol Analogues, the Putative Cyclooxygenase-2 Inhibitors

Characterizing the relationship between the chemical structures of drugs and their activities on primary cultures of pediatric solid tumors

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