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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.

No MeSH data available.


Distributions of the docking scores for the inhibitors and non-inhibitors based on (A) 2WQB, Glide SP docking, (B) 2WQB, Glide XP docking, (C) 3L8P, Glide SP docking and (D) 3L8P, Glide XP docking.
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f2: Distributions of the docking scores for the inhibitors and non-inhibitors based on (A) 2WQB, Glide SP docking, (B) 2WQB, Glide XP docking, (C) 3L8P, Glide SP docking and (D) 3L8P, Glide XP docking.

Mentions: At present, two DFG-in structures (Type-I) of Tie-2 complexes (PDB entries: 2WQB and 3L8P)3334 are available in RCSB Protein Data Bank35. Both crystal structures were firstly assessed for their ability to distinguish the known inhibitors from non-inhibitors of Tie-2 using two different scoring modes of docking (Glide SP and XP). The distributions of the docking scores for both inhibitors and non-inhibitors were plotted in Fig. 2. The student’s t-test was used to assess the significance of the difference between two sets of docking scores with the associated probability (p value). Moreover, the AUC values (area under curve) of the ROC (receiver operating characteristic) curves for both crystals based on the docking scores were also plotted in Supplementary Fig. S3 to quantitatively evaluate the prediction accuracy. We can find that the p values for 3L8P are much lower than those for 2WQB and the AUC values from SP and XP docking of 3L8P crystal are both higher than those from 2WQB, indicating that the discrimination power of molecular docking based on 3L8P is much higher. Thus, the crystal structure of 3L8P was employed in our VS campaign. For both 2WQB and 3L8P crystals, the performance of Glide XP docking is slightly better than that of SP docking, but the computational cost of XP docking is relatively much higher. Therefore, the Glide SP docking was utilized in the first-round screening of the entire ChemBridge database (~1,020,000 compounds). Afterwards the top-ranked 100,000 compounds from the SP docking were submitted to the second-round screening using the Glide XP docking, and the top-ranked 2,000 compounds were then saved.


In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates
Distributions of the docking scores for the inhibitors and non-inhibitors based on (A) 2WQB, Glide SP docking, (B) 2WQB, Glide XP docking, (C) 3L8P, Glide SP docking and (D) 3L8P, Glide XP docking.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Distributions of the docking scores for the inhibitors and non-inhibitors based on (A) 2WQB, Glide SP docking, (B) 2WQB, Glide XP docking, (C) 3L8P, Glide SP docking and (D) 3L8P, Glide XP docking.
Mentions: At present, two DFG-in structures (Type-I) of Tie-2 complexes (PDB entries: 2WQB and 3L8P)3334 are available in RCSB Protein Data Bank35. Both crystal structures were firstly assessed for their ability to distinguish the known inhibitors from non-inhibitors of Tie-2 using two different scoring modes of docking (Glide SP and XP). The distributions of the docking scores for both inhibitors and non-inhibitors were plotted in Fig. 2. The student’s t-test was used to assess the significance of the difference between two sets of docking scores with the associated probability (p value). Moreover, the AUC values (area under curve) of the ROC (receiver operating characteristic) curves for both crystals based on the docking scores were also plotted in Supplementary Fig. S3 to quantitatively evaluate the prediction accuracy. We can find that the p values for 3L8P are much lower than those for 2WQB and the AUC values from SP and XP docking of 3L8P crystal are both higher than those from 2WQB, indicating that the discrimination power of molecular docking based on 3L8P is much higher. Thus, the crystal structure of 3L8P was employed in our VS campaign. For both 2WQB and 3L8P crystals, the performance of Glide XP docking is slightly better than that of SP docking, but the computational cost of XP docking is relatively much higher. Therefore, the Glide SP docking was utilized in the first-round screening of the entire ChemBridge database (~1,020,000 compounds). Afterwards the top-ranked 100,000 compounds from the SP docking were submitted to the second-round screening using the Glide XP docking, and the top-ranked 2,000 compounds were then saved.

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.