Dataset Information

Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies.

ABSTRACT: Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed with axitinib and was subsequently validated and employed as a 3D query to retrieve the candidate compounds with the key inhibitory features. The model was escalated to molecular docking studies resulting in seven candidate compounds. The molecular docking studies revealed that the seven compounds displayed a higher dock score than the reference-cocrystallised compound. The GROningen MAchine for Chemical Simulations (GROMACS) package guided molecular dynamics (MD) results determined their binding mode and affirmed stable root mean square deviation. Furthermore, these compounds have preserved their key interactions with the residues Glu885, Glu917, Cys919 and Asp1046. The obtained findings deem that the seven compounds could act as novel anti-angiogenic inhibitors and may further assist as the prototype in designing and developing new inhibitors.

SUBMITTER: Rampogu S

PROVIDER: S-EPMC6468367 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies.

Rampogu Shailima S Baek Ayoung A Park Chanin C Parate Shraddha S Parameswaran Saravanan S Park Yohan Y Shaik Baji B Kim Ju Hyun JH Park Seok Ju SJ Lee Keun Woo KW

Cells 20190321 3

Angiogenesis is defined as the formation of new blood vessels and is a key phenomenon manifested in a host of cancers during which tyrosine kinases play a crucial role. Vascular endothelial growth factor receptor-2 (VEGFR-2) is pivotal in cancer angiogenesis, which warrants the urgency of discovering new anti-angiogenic inhibitors that target the signalling pathways. To obtain this objective, a structure-based pharmacophore model was built from the drug target VEGFR-2 (PDB code: 4AG8), complexed ...[more]

PMID: 30901950

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Project description:The prediction of biological targets of bioactive molecules from machine-readable materials can be routinely performed by computational target prediction tools (CTPTs). However, the prediction of biological targets of bioactive molecules from non-digital materials (e.g., printed or handwritten documents) has not been possible due to the complex nature of bioactive molecules and impossibility of employing computations. Improving the target prediction accuracy is the most important challenge for computational target prediction. A minimum structure is identified for each group of neighbor molecules in the proposed method. Each group of neighbor molecules represents a distinct structural class of molecules with the same function in relation to the target. The minimum structure is employed as a query to search for molecules that perfectly satisfy the minimum structure of what is guessed crucial for the targeted activity. The proposed method is based on chemical similarity, but only molecules that perfectly satisfy the minimum structure are considered. Structurally related bioactive molecules found with the same minimum structure were considered as neighbor molecules of the query molecule. The known target of the neighbor molecule is used as a reference for predicting the target of the neighbor molecule with an unknown target. A lot of information is needed to identify the minimum structure, because it is necessary to know which part(s) of the bioactive molecule determines the precise target or targets responsible for the observed phenotype. Therefore, the predicted target based on the minimum structure without employing the statistical significance is considered as a reliable prediction. Since only molecules that perfectly (and not partly) satisfy the minimum structure are considered, the minimum structure can be used without similarity calculations in non-digital materials and with similarity calculations (perfect similarity) in machine-readable materials. Nine tools (PASS online, PPB, SEA, TargetHunter, PharmMapper, ChemProt, HitPick, SuperPred, and SPiDER), which can be used for computational target prediction, are compared with the proposed method for 550 target predictions. The proposed method, SEA, PPB, and PASS online, showed the best quality and quantity for the accurate predictions.

Dataset Information

Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies.

Publications

Discovery of Small Molecules that Target Vascular Endothelial Growth Factor Receptor-2 Signalling Pathway Employing Molecular Modelling Studies.

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