Mixing Pharmacophore Modeling and Classical QSAR Analysis as Powerful Tool for Lead Discovery

Taha, Mutasem O.

doi:10.5772/20993

Cited by 5 publications

(2 citation statements)

References 61 publications

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“…ROC curves were plotted by considering the highest score (fit value against the tested pharmacophore) of an active molecule as the first threshold then counting the number of decoy compounds within this cut-off value, and the corresponding sensitivity and specificity pair is calculated. This process is repeated using the active molecule possessing the second highest score and so forth, until the scores of all active compounds are considered as selection cut-off values rate [79,80,93,94]. Details of ROC analysis are shown in Section S4 under Supplementary Materials.…”

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confidence: 99%

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

2020

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Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied—aiming to identify novel Aurora-A kinase inhibitors—using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead 85(NCI 14040) molecule after 72 h of incubation, scoring IC50 values of 3.5–11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC50 on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.

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confidence: 99%

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

2020

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“…Compound II is a stilbene derivative with an IC 50 value of 15 μM against COX-1 and a selectivity index of around 200 folds [ 13 ]. Drawing from the mixed pharmacophore theory [ 14 ], novel Schiff base analogues were designed based on two pharmacophoric regions ( Figure 1 ). Region I is a benzene sulfonamide moiety inspired by the structure of compound I.…”

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confidence: 99%

Synthesis, Docking, and DFT Studies on Novel Schiff Base Sulfonamide Analogues as Selective COX-1 Inhibitors with Anti-Platelet Aggregation Activity

Aziz,

Nafie,

Hanna

et al. 2024

Pharmaceuticals

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Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, 10–13, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds 10–13 were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds 10–13. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is E. Biological results revealed that all the screened compounds 10–13 might serve as selective COX-1 inhibitors. They showed IC50 values ranging from 0.71 μM to 4.82 μM against COX-1 and IC50 values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC50 values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC50 value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC50 values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC50 value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of E-forms with respect to Z-forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.

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Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

2023

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Mixing Pharmacophore Modeling and Classical QSAR Analysis as Powerful Tool for Lead Discovery

Cited by 5 publications

References 61 publications

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

Structure-Based Discovery and Bioactivity Evaluation of Novel Aurora-A Kinase Inhibitors as Anticancer Agents via Docking-Based Comparative Intermolecular Contacts Analysis (dbCICA)

Synthesis, Docking, and DFT Studies on Novel Schiff Base Sulfonamide Analogues as Selective COX-1 Inhibitors with Anti-Platelet Aggregation Activity

Development of phosphoinositide 3-kinase delta (PI3Kδ) inhibitors as potential anticancer agents through the generation of ligand-based pharmacophores and biological screening

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