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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.


MM/GBSA decomposition analysis of the energetic contributions of the dominating amino acids on a per-residue basis for compounds TP-C2-9, TP-C3-2, TP-C3-3, TP-C3-21 and TP-C3-22.The diagram was generated based on the average structures from the last stable 3 ns conformations of each MD simulation.
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f7: MM/GBSA decomposition analysis of the energetic contributions of the dominating amino acids on a per-residue basis for compounds TP-C2-9, TP-C3-2, TP-C3-3, TP-C3-21 and TP-C3-22.The diagram was generated based on the average structures from the last stable 3 ns conformations of each MD simulation.

Mentions: The inhibitory activity of compound TP-C3-3 (IC50 = 2.82 μM) is only slightly decreased compared to that of TP-C2-9, where two methoxy groups are removed from the R2 phenyl ring. This indicates that the removal of methoxy groups has little influence on ligand binding. However, replacement of 3-methyl group by 4-tert-butyl in R1 ring (compound TP-C3-2) leads to~10 fold decreases in activity compared with compound TP-C3-3. To gain rational insights into the difference of the binding modes, MM/GBSA binding energy calculations and decomposition analysis based on MD simulations were performed by examining the contribution of each residue to binding. Figure 7 illustrated the energetic contributions of the dominating residues from the MM/GBSA decomposition analysis. We can find that the contributions of most residues for both compounds TP-C2-9 and TP-C3-3 are similar, implying that removal of methoxy groups from R2 ring does not affect the main interactions between inhibitors and Tie-2. For the binding of compound TP-C3-2 (see Supplementary Fig. S1), several critical interaction patterns are influenced, especially the arene-H contacts with the residues Ile902 and Leu971. As illustrated in Fig. 7, the contributions of Ile902 and Leu971 for TP-C3-2, which are dominated by the non-polar interactions, are obviously smaller than those for TP-C3-3. In addition, the impaired interactions with Tyr904 also account for the inferior binding affinity of TP-C3-2. Interestingly, the binding to Asp982, where arene-H interactions can be observed, is found stronger than both compounds TP-C2-9 and TP-C3-3, however, this cannot make up for the decreased binding affinity to other amino acids.


In Silico Exploration for Novel Type-I Inhibitors of Tie-2/TEK: The Performance of Different Selection Strategy in Selecting Virtual Screening Candidates
MM/GBSA decomposition analysis of the energetic contributions of the dominating amino acids on a per-residue basis for compounds TP-C2-9, TP-C3-2, TP-C3-3, TP-C3-21 and TP-C3-22.The diagram was generated based on the average structures from the last stable 3 ns conformations of each MD simulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: MM/GBSA decomposition analysis of the energetic contributions of the dominating amino acids on a per-residue basis for compounds TP-C2-9, TP-C3-2, TP-C3-3, TP-C3-21 and TP-C3-22.The diagram was generated based on the average structures from the last stable 3 ns conformations of each MD simulation.
Mentions: The inhibitory activity of compound TP-C3-3 (IC50 = 2.82 μM) is only slightly decreased compared to that of TP-C2-9, where two methoxy groups are removed from the R2 phenyl ring. This indicates that the removal of methoxy groups has little influence on ligand binding. However, replacement of 3-methyl group by 4-tert-butyl in R1 ring (compound TP-C3-2) leads to~10 fold decreases in activity compared with compound TP-C3-3. To gain rational insights into the difference of the binding modes, MM/GBSA binding energy calculations and decomposition analysis based on MD simulations were performed by examining the contribution of each residue to binding. Figure 7 illustrated the energetic contributions of the dominating residues from the MM/GBSA decomposition analysis. We can find that the contributions of most residues for both compounds TP-C2-9 and TP-C3-3 are similar, implying that removal of methoxy groups from R2 ring does not affect the main interactions between inhibitors and Tie-2. For the binding of compound TP-C3-2 (see Supplementary Fig. S1), several critical interaction patterns are influenced, especially the arene-H contacts with the residues Ile902 and Leu971. As illustrated in Fig. 7, the contributions of Ile902 and Leu971 for TP-C3-2, which are dominated by the non-polar interactions, are obviously smaller than those for TP-C3-3. In addition, the impaired interactions with Tyr904 also account for the inferior binding affinity of TP-C3-2. Interestingly, the binding to Asp982, where arene-H interactions can be observed, is found stronger than both compounds TP-C2-9 and TP-C3-3, however, this cannot make up for the decreased binding affinity to other amino acids.

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.