Vascular Endothelial Growth Factor Receptor (VEGFR-2)/KDR Inhibitors: Medicinal Chemistry Perspective

Modi, Siddharth J.; Kulkarni, Vithal M.

doi:10.1016/j.medidd.2019.100009

Cited by 201 publications

(152 citation statements)

References 176 publications

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“…The second protein is Vascular endothelial growth factor receptor 2 (VEGFR2). VEGFR2 is a cell-surface receptor with tyrosine kinase activity 48 . Three growth factors bind to VEGFR2: VEGFA, VEGFC, and VEGFD.…”

Section: Resultsmentioning

confidence: 99%

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Grechishnikova

2021

Sci Rep

139

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Drug discovery for a protein target is a very laborious, long and costly process. Machine learning approaches and, in particular, deep generative networks can substantially reduce development time and costs. However, the majority of methods imply prior knowledge of protein binders, their physicochemical characteristics or the three-dimensional structure of the protein. The method proposed in this work generates novel molecules with predicted ability to bind a target protein by relying on its amino acid sequence only. We consider target-specific de novo drug design as a translational problem between the amino acid “language” and simplified molecular input line entry system representation of the molecule. To tackle this problem, we apply Transformer neural network architecture, a state-of-the-art approach in sequence transduction tasks. Transformer is based on a self-attention technique, which allows the capture of long-range dependencies between items in sequence. The model generates realistic diverse compounds with structural novelty. The computed physicochemical properties and common metrics used in drug discovery fall within the plausible drug-like range of values.

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Section: Resultsmentioning

confidence: 99%

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Grechishnikova

2021

Sci Rep

139

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“…Moreover, the contacts distribution involving this compound and Thr916 or Glu917 was retained as well (Figures S23-S26; Supplementary Material). Considering the structural features of azoles 1-9, we should emphasise that the MD fluctuations concerned the chlorine atom (1), heterocyclic systems on position 5 of indazole (2-7), and tosyl ring (1)(2)(3)(4)(5)(6)(7)(8)(9).…”

Section: Molecular Dynamics Calculationsmentioning

confidence: 99%

“…Activation of VEGFR2 not only stimulates angiogenesis but also turns on other signalling pathways that include, inter alia, the PI3K-AKT-mTor pathway responsible for cell survival [ 3 , 4 , 5 , 6 ]. Overexpression of VEGFR2 is a typical feature of solid tumours, especially carcinomas and gliomas (bladder carcinoma, brain glioma, breast, cervical, colon, kidney, non-small celled lung, ovarian, pancreatic, and prostate cancers), which need a lattice of new blood vessels to grow beyond a 1–2 mm diameter and spread metastases [ 7 ]. However, there is evidence that angiogenesis plays a significant role in the progression of haematological malignancies as well [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase

Czaja

Kujawski

Śliwa

et al. 2020

IJMS

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Vascular endothelial growth factor receptor 2 (VEGFR2) is a key receptor in the angiogenesis process. The VEGFR2 expression is upregulated in many cancers so this receptor is an important target for anticancer agents. In the present paper, we analyse interactions of several dimeric indazoles, previously investigated for anticancer activity, with the amino acids present in the VEGFR2 binding pocket. Using the docking method and MD simulations as well as theoretical computations (SAPT0, PIEDA, semi-empirical PM7), we confirmed that these azoles can efficiently bind into the kinase pocket and their poses can be stabilised by the formation of hydrogen bonds, π–π stacking, π–cation, and hybrid interactions with some amino acids of the kinase cavity like Ala866, Lys868, Glu885, Thr916, Glu917, and Phe918.

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“…[8,9,[24][25][26] Several VEGFR-2 inhibitors have already been reported in the literature, showing different molecular patterns and distinct pharmacological profiles. [27,28] The US Food and Drug Administration (FDA) has already approved 48 small molecular entities with kinase inhibitory properties, [29] among which there are several VEGFR-2 inhibitors, for example sorafenib [30,31] 1, sunitinib [32][33][34][35] 2, axitinib [36][37][38] 3, and cabozantinib [39,40] 4 (Figure 1). [41,42] Vatalanib (5; PTK787; Figure 1) is one of the most potent and selective first-generation VEGFR inhibitors, consisting of an aminophthalazine derivative synthesized in 2000 by Novartis.…”

Section: Introductionmentioning

confidence: 99%

Novel VEGFR‐2 inhibitors with an N‐acylhydrazone scaffold

Pauli

Martins

Paschoalin

et al. 2020

Archiv der Pharmazie

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Vascular endothelial growth factor receptor 2 (VEGFR-2) is a tyrosine kinase that mediates a large number of cell responses associated with angiogenesis. The control of the angiogenic pathway in tumorigenesis by the inhibition of VEGFR-2 is considered a promising therapeutic strategy for the prevention and control of solid tumor growth. In this study, the design, synthesis, and biological evaluation of a novel series of VEGFR-2 inhibitors with an N-acylhydrazone (NAH) scaffold (9a-h) are reported. The molecular design is validated by docking studies and by in vitro inhibitory activity assays. Compounds 9b, 9c, 9d, and 9f effectively inhibited neovascularization induced by VEGF in the chorioallantoic membrane assay. Thus, these NAH derivatives are promising antiangiogenic prototypes.

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Vascular Endothelial Growth Factor Receptor (VEGFR-2)/KDR Inhibitors: Medicinal Chemistry Perspective

Cited by 201 publications

References 176 publications

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Transformer neural network for protein-specific de novo drug generation as a machine translation problem

Theoretical Investigations on Interactions of Arylsulphonyl Indazole Derivatives as Potential Ligands of VEGFR2 Kinase

Novel VEGFR‐2 inhibitors with an N‐acylhydrazone scaffold

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