Discovery of novel Flt3 inhibitory chemotypes through extensive ligand-based and new structure-based pharmacophore modelling methods

Abutayeh, Reem Fawaz; Taha, Mutasem O.

doi:10.1016/j.jmgm.2019.01.011

Cited by 15 publications

(12 citation statements)

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“…To understand the interactions associated in ligand binding into Aurora-A kinase, we implemented the innovative structure-based 3D-QSAR methodology; docking-based comparative intermolecular contacts analysis (dbCICA) [51,56,57,[60][61][62][63][64][65][66][67] as a tool to study how the seventy-nine Aurora-A kinase inhibitors (Table S1 in Supplementary Material) bind into Aurora-A binding pocket. dbCICA modeling was used to create successful pharmacophore hypotheses that highlighted the critical binding interactions engaged in ligand-Aurora-A kinase binding.…”

Section: Structure-based Molecular Modelingmentioning

confidence: 99%

“…The resulting docked poses (i.e., of hits) were analyzed to identify their binding critical contacts. The activity of each hit was predicted by using the sums of critical contacts as identified by the respective dbCICA model (Tables 1 and 2) through substituting the sum of contacts with binding-site atoms in the corresponding dbCICA-regression equations [56,57,[60][61][62][63][64][65][66][67].…”

Section: In-silico Screening and Fret Based Enzyme Inhibition Assaymentioning

confidence: 99%

“…The docking experiment yielded 28 sets of docked poses (in SD format) that represent the combination of seven scoring functions, unionized vs. ionized ligands, un-hydrous vs. hydrous binding sites. The highest scoring docked pose for each inhibitor was chosen to be used in subsequent (dbCICA) modeling [56,57,[60][61][62][63][64][65][66][67].…”

Section: Docking and Scoringmentioning

confidence: 99%

“…At last, pharmacophores are used for in silico database searching, aiming to find novel hits [51,56,57,[60][61][62][63][64][65][66][67].…”

Section: Introductionmentioning

confidence: 99%

“…dbCICA was applied previously to discover new heat shock protein 90 inhibitors, new glycogen phosphorylase inhibitors, new fungal N-myristoyl transferase inhibitors, new CPK1 inhibitors, new FGFR1 inhibitors, new 3CLpro inhibitors, new Acetylcholinesterase inhibitors, new Gyrase b, new Flt3 and lately new JNK3 inhibitors [51][52][53][54][55][56][57][60][61][62][63][64][65][66][67].…”

Section: Introductionmentioning

confidence: 99%

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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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