<i>In silico</i> studies on potential TNKS inhibitors: a combination of pharmacophore and 3D-QSAR modelling, virtual screening, molecular docking and molecular dynamics

Liu, Jianxin; Feng, Kairui; Ren, Yujie

doi:10.1080/07391102.2018.1528887

Cited by 9 publications

(6 citation statements)

References 46 publications

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“…Recently, the same tetrazolo[1,5-a]quinoxalin-4-amine series from which 28 was derived was studied in silico, including 3D-QSAR modeling and molecular dynamics simulation. 158 The results would inform the further design of novel chemical scaffolds for tankyrase inhibitors.…”

Section: Small-molecule Inhibitors Of Tankyrases: From Discovery To T...mentioning

confidence: 98%

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

Yang

Sykes

et al. 2022

J. Med. Chem.

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Tankyrases are multifunctional poly(adenosine diphosphate-ribose) polymerases that regulate diverse biological processes including telomere maintenance and cellular signaling. These processes are often implicated in a number of human diseases, with cancer being the most prevalent example. Accordingly, tankyrase inhibitors have gained increasing attention as potential therapeutics. Since the discovery of XAV939 and IWR-1 as the first tankyrase inhibitors over two decades ago, tankyrase-targeted drug discovery has made significant progress. This review starts with an introduction of tankyrases, with emphasis placed on their cancer-related functions. Small-molecule inhibitors of tankyrases are subsequently delineated based on their distinct modes of binding to the enzymes. In addition to inhibitors that compete with oxidized nicotinamide adenine dinucleotide (NAD+) for binding to the catalytic domain of tankyrases, non-NAD+-competitive inhibitors are detailed. This is followed by a description of three clinically trialled tankyrase inhibitors. To conclude, some of challenges and prospects in developing tankyrase-targeted cancer therapies are discussed.

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Section: Small-molecule Inhibitors Of Tankyrases: From Discovery To T...mentioning

confidence: 98%

Small-Molecule Inhibitors of Tankyrases as Prospective Therapeutics for Cancer

Yang

Sykes

et al. 2022

J. Med. Chem.

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“…In total, 51 3,4,5-trisubstituted 4H-1,2,4-triazole derivatives, as reported tankyrase-2 (TNKS-2) inhibitors, were collected from papers published by the research group lead by Michael Shultz at Novartis Institutes of Biomedical Research during 2012-2013 for the generation of 3D-QSAR models using the Sybyl X software [15,16]. To perform 3D-QSAR, the requisite dependent variable of pIC 50 (or -logIC 50 ) values were generated using transform data tool from the reported TNKS-2 IC 50 (inhibitory concentration) values of all selected triazole derivatives [11,21,22]. These pIC 50 values were made homologous and widely acceptable covering 4 log units.…”

Section: Data Sets With Their Biological Activitymentioning

confidence: 99%

“…Several methods were available, i.e., rigid body (distill)-based, pharmacophorebased, and docking-based alignment to understand and thereby to compare the effect of different substitutions as a function for the corresponding modulation of biological activity [21]. Alignment of the compounds depicted direct correlation with statistical results of 3D-QSAR studies; where results from CoMFA and CoMSIA showed requisite and favorable statistical variations based on t he type of alignment [11,23,24]. Alignment-I, as shown in Fig.…”

Section: Molecular Alignmentmentioning

confidence: 99%

“…Alignment-III, a Fig. 1 Reported tankyrase Inhibitors at an early phase of discovery docking-based alignment, was performed by using the Surflex-Dock module of Sybyl X using the results of docking studies which were carried out with all 51 ligand molecules using the X-ray crystal structure of the tankyrase-2 enzyme [11,15,16] from RCSB protein data bank (PDB: 3U9H). The result of alignment based on docking is depicted in Fig.…”

Section: Molecular Alignmentmentioning

confidence: 99%

“…Particularly, G0007-LK (5), which is a structurally different substituted 4H-1,2,4-triazole containing nonlactam selective tankyrase inhibitor, achieved nanomolar tankyrase inhibitory concentrations and good pharmacokinetic profile [10]. Liu et al reported 3D-QSAR model for designing novel tankyrase inhibitors by considering a reported series of tetrazoloquinoxaline derivatives [11].…”

Section: Introductionmentioning

confidence: 99%

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New molecular insights into dual inhibitors of tankyrase as Wnt signaling antagonists: 3D-QSAR studies on 4H-1,2,4-triazole derivatives for the design of novel anticancer agents

2020

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Genetic mutations in APC or CNTBB1 gene with aberrant canonical Wnt/β-catenin pathway are responsible for more than 90% of colorectal carcinogenesis. Tankyrases (TNKS) are known to downregulate Wnt signaling by stabilizing AXIN protein through poly(ADP ribose)polymerization or PARSylation process and subsequently, promoting degradation of intracellular β-catenin. Tankyrase enzymes are modulated by a range of known inhibitors that bind individually to any of the nicotinamide or induced adenosine pockets or as dual binding antagonists. Hence, for designing dual tankyrase inhibitors as Wnt signaling antagonist; we carried out 3D-QSAR studies using a data set of 51 molecules of reported 3,4,5-trisubstituted 4H-1,2,4-triazole derivatives. These reported 51 molecules were divided into a training set (39 molecules) and test set (12 molecules), aligned and subjected to generate CoMFA, CoMSIA, and HQSAR models. CoMFA analysis showed q 2 value of 0.694, r 2 ncv value of 0.991 and r 2 pred value of 0.641. Optimized CoMSIA analysis (SEHA) showed q 2 value of 0.624, r 2 ncv value of 0.909 and r 2 pred value of 0.850. Both internal and external validations were performed for generated models of CoMFA and CoMSIA (SEHA) and satisfactory results were obtained. HQSAR analysis showed q 2 , r 2 , and r 2 pred values of 0.781, 0.901, and 0.811, respectively. Applicability domain was also found to be satisfactory with all compounds falling within the range and no outlier was observed. Contour maps from all studies provided significant results with identification of desired spatial arrangement of different atoms or functional groups in a molecule. Triazole ring system-based molecules were reported as potent tankyrase inhibitors. These noteworthy results were employed for the design of different triazole derivatives as potent tankyrase inhibitors, wherein a series of 20 different molecules were designed for evaluation of their potentials as novel tankyrase inhibitors.

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