Dataset Information

GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents.

ABSTRACT: A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-?1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin. To investigate whether the thieno[2,3-b]pyridines modulate G protein-coupled receptors (GPCRs) other than A2A, a screen against 168 GPCRs was conducted. According to the results, ligand 1 modulates five receptors in the low µM region, four as an antagonist; CRL-RAMP3 (IC50-11.9 µM), NPSR1B (IC50-1.0 µM), PRLHR (IC50-9.3 µM), and CXCR4 (IC50-6.9 µM). Finally, one agonist, GPRR35, was found (EC50 of 7.5 µM). Molecular modelling showed good binding to all of the receptors investigated; however, none of these surpass the A2A receptor. Furthermore, the newly-identified receptors are relatively modestly expressed in the cancer cell lines most affected by the thieno[2,3-b]pyridines, making them less likely to be the main targets of the mechanism of action for this compound class. Nevertheless, new modulators against GPCRs are of an interest as potential hits for further drug development.

SUBMITTER: Zafar A

PROVIDER: S-EPMC6149898 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents.

Zafar Ayesha A Sari Suat S Leung Euphemia E Pilkington Lisa I LI van Rensburg Michelle M Barker David D Reynisson Jóhannes J

Molecules (Basel, Switzerland) 20171218 12

A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-<i>b</i>]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-δ1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible ...[more]

PMID: 29258235

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Project description:In this work, new thieno[2,3-d]pyrimidine-derived compounds possessing potential anticancer activities were designed and synthesized to target VEGFR-2. The thieno[2,3-d]pyrimidine derivatives were tested in vitro for their abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two types of cancer cells, MCF-7 and HepG2. Compound 18 exhibited the strongest anti-VEGFR-2 potential with an IC50 value of 0.084 μM. Additionally, it displayed excellent proliferative effects against MCF-7 and HepG2 cancer cell lines, with IC50 values of 10.17 μM and 24.47 μM, respectively. Further studies revealed that compound 18 induced cell cycle arrest in G2/M phase and promoted apoptosis in MCF-7 cancer cells. Apoptosis was stimulated by compound 18 by increasing BAX (3.6-fold) and decreasing Bcl-2 (3.1-fold). Additionally, compound 18 significantly raised the levels of caspase-8 (2.6-fold) and caspase-9 (5.4-fold). Computational techniques were also used to investigate the VEGFR-2-18 complex at a molecular level. Molecular docking and molecular dynamics simulations were performed to assess the structural and energetic features of the complex. The protein-ligand interaction profiler analysis identified the 3D interactions and binding conformation of the VEGFR-2-18 complex. Essential dynamics (ED) study utilizing principal component analysis (PCA) described the protein dynamics of the VEGFR-2-18 complex at various spatial scales. Bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-18 complex. In addition, the DFT studies provided insights into the structural and electronic properties of compound 18. Finally, computational ADMET and toxicity studies were conducted to evaluate the potential of the thieno[2,3-d]pyrimidine derivatives for drug development. The results of the study suggested that compound 18 could be a promising anticancer agent that may provide effective treatment options for cancer patients. Furthermore, the computational techniques used in this research provided valuable insights into the molecular interactions of the VEGFR-2-18 complex, which may guide future drug design efforts. Overall, this study highlights the potential of thieno[2,3-d]pyrimidine derivatives as a new class of anticancer agents and provides a foundation for further research in this area.

Dataset Information

GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents.

Publications

GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents.

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