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In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates

View Article: PubMed Central - PubMed

ABSTRACT

The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered. To directly compare the efficiency between different filtering strategies in selecting VS candidates, two methods were separately carried out to screen the same chemical library, and the selected VS candidates were then experimentally assessed by in vitro enzymatic assays. The results demonstrate that the hit rate is improved when stricter drug-likeness criteria and less number of molecules for clustering analysis are used, and meanwhile, the molecular diversity of the compounds still maintains. As a case study of TIE-2, the information presented in this work underscores the importance of selecting an appropriate selection strategy in VS campaign, and the novel inhibitors identified and the detailed binding modes of action provide a starting point for further hit-to-lead optimization process.

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Comparison of hit percentage between candidates from two filtering strategies with different cutoff values of inhibition rates.
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f4: Comparison of hit percentage between candidates from two filtering strategies with different cutoff values of inhibition rates.

Mentions: In order to assess the biological inhibitory activity of the VS compounds, Z’-Lyte enzymatic activity assay based on FRET (Fluorescence Resonance Energy Transfer) technology was developed as described above. The Tie-2 inhibitor (CAS: 948557–43–5) was previously reported as a tool inhibitor that can potently inhibit Tie-2 activity with an IC50 value of 0.25 μM, and was used as a positive control inhibitor in our study. The tested inhibitory activity of this Tie-2 inhibitor is 0.31 μM, which is in good agreement with the ref. 40. At first, all the compounds obtained from both filtering strategies were preliminary screened for their ability to inhibit Tie-2 kinase activity at the concentration of 10 μg/mL. The results were summarized and plotted in Fig. 3 and Fig. 4. It is easy to find that the performance of the candidates chosen from the clustering of the top-ranked 200 compounds is better than those chosen from the clustering of the top-ranked 1,000 compounds. The probability p value of the two sets is 0.00018 indicating that they are statistically different. As we can see in Fig. 4, over 80 percentage of the purchased compounds from Strategy 2 were found to inhibit ≥50% Tie-2 activity at 10 μg/mL, and ~40% compounds can inhibit ≥80% Tie-2 activity. However, only ~20% compounds from Strategy 1 were observed to inhibit ≥50% Tie-2 activity, and <10% compounds were found to inhibit ≥80% activity. This indicates that the hit rate from Strategy 2 is much higher than that from Strategy 1. Different selection strategies in selecting the same 2,000 VS candidates have a pronounced influence on the overall hit rates of the active compounds. The results demonstrate that the hit rates can be well improved when stricter drug-likeness criteria and top-200 rather than top-1000 compounds for clustering analysis are used.


In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates
Comparison of hit percentage between candidates from two filtering strategies with different cutoff values of inhibition rates.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5120310&req=5

f4: Comparison of hit percentage between candidates from two filtering strategies with different cutoff values of inhibition rates.
Mentions: In order to assess the biological inhibitory activity of the VS compounds, Z’-Lyte enzymatic activity assay based on FRET (Fluorescence Resonance Energy Transfer) technology was developed as described above. The Tie-2 inhibitor (CAS: 948557–43–5) was previously reported as a tool inhibitor that can potently inhibit Tie-2 activity with an IC50 value of 0.25 μM, and was used as a positive control inhibitor in our study. The tested inhibitory activity of this Tie-2 inhibitor is 0.31 μM, which is in good agreement with the ref. 40. At first, all the compounds obtained from both filtering strategies were preliminary screened for their ability to inhibit Tie-2 kinase activity at the concentration of 10 μg/mL. The results were summarized and plotted in Fig. 3 and Fig. 4. It is easy to find that the performance of the candidates chosen from the clustering of the top-ranked 200 compounds is better than those chosen from the clustering of the top-ranked 1,000 compounds. The probability p value of the two sets is 0.00018 indicating that they are statistically different. As we can see in Fig. 4, over 80 percentage of the purchased compounds from Strategy 2 were found to inhibit ≥50% Tie-2 activity at 10 μg/mL, and ~40% compounds can inhibit ≥80% Tie-2 activity. However, only ~20% compounds from Strategy 1 were observed to inhibit ≥50% Tie-2 activity, and <10% compounds were found to inhibit ≥80% activity. This indicates that the hit rate from Strategy 2 is much higher than that from Strategy 1. Different selection strategies in selecting the same 2,000 VS candidates have a pronounced influence on the overall hit rates of the active compounds. The results demonstrate that the hit rates can be well improved when stricter drug-likeness criteria and top-200 rather than top-1000 compounds for clustering analysis are used.

View Article: PubMed Central - PubMed

ABSTRACT

The receptor tyrosine kinase Tie-2 is involved in vessel remodeling and maturation, and has been regarded as a potential target for the treatment of various solid tumors. The absence of novel, potent and selective inhibitors severely hampers the understanding of the therapeutic potential of Tie-2. In the present work, we describe the discovery of novel type-I inhibitors of Tie-2 by structure-based virtual screening. Preliminary SAR was also performed based on one active compound, and several novel inhibitors with low micro-molar affinity were discovered. To directly compare the efficiency between different filtering strategies in selecting VS candidates, two methods were separately carried out to screen the same chemical library, and the selected VS candidates were then experimentally assessed by in vitro enzymatic assays. The results demonstrate that the hit rate is improved when stricter drug-likeness criteria and less number of molecules for clustering analysis are used, and meanwhile, the molecular diversity of the compounds still maintains. As a case study of TIE-2, the information presented in this work underscores the importance of selecting an appropriate selection strategy in VS campaign, and the novel inhibitors identified and the detailed binding modes of action provide a starting point for further hit-to-lead optimization process.

No MeSH data available.