atp binding site
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2022 ◽  
Author(s):  
Rania M. Gomaa ◽  
Magda A. El-Sayed ◽  
Khalid Bashir Selim

Abstract New compounds of 4-anilino-6-substituted quinazoline were designed, synthesized and tested for their EGFR-TK and tumor growth inhibitory activities. The synthesized compounds were appended with amides 6 and 7, dithiocarbamate ester 8a–f or urea/thiourea 9–12 moieties at C-6 of the quinazoline ring to work as extra hydrogen bond acceptors. All the synthesized compounds were effective against EGFR-TK activity, particularly, derivatives 8a, 8f and 9 with IC50 values of 0.14±0.003, 0.119±0.003, and 0.115±0.002 μM, respectively, showed the best activities. The three compounds were further assayed for their cytotoxicity against MCF-7, H-69, SKOV-3 and LS-174T cell lines. Multikinase enzymes inhibition activity of compound 9 was further screened including VEGFR-2, c-MER, c-MET and Her-2. Compounds 8a, 8f, and 9 were docked into the ATP binding site of EGFR-TK which also had resemblance binding pattern to erlotinib with extra binding mode with Cys-773 at the gatekeeper of the enzyme. Cell cycle analyses of MCF-7 cells treated with 8a and 9 was measured in addition to other related factors such as Bax, Bcl-2, caspase-9, and PARP-1.


Inorganics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 3
Author(s):  
Facundo Tarasi ◽  
Priscila Ailín Lanza ◽  
Valeria Ferretti ◽  
Gustavo Alberto Echeverría ◽  
Oscar Enrique Piro ◽  
...  

The main goal of this work was to report the synthesis, characterization, and cytotoxicity study of a novel copper(II)-sunitinib complex, CuSun. It has been synthesized and characterized in solid state and in solution by different methods (such as DFT, FTIR, Raman, UV-vis, EPR, NMR, etc.). The solid-state molecular structure of trichlorosunitinibcopper(II), where sunitinib: N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide, for short Cu(Sun)Cl3, was determined by X-ray diffraction. It crystallizes in the triclinic space group P-1 with a = 7.9061(5) Å, b = 12.412(1) Å, c = 13.7005(8) Å, α = 105.021(6)°, β = 106.744(5)°, γ = 91.749(5)°, and Z = 2 molecules per unit cell. Also, we have found π-π interactions and classic and non-classic H-bonds in the crystal structure by using Hirshfeld surface analysis. In the speciation studies, the complex has dissociated in protonated sunitinib and chlorocomplex of copper(II), according to 1HNMR, EPR, UV-vis and conductimetric analysis. Molecular docking of the complex in both, ATP binding site and allosteric site of VEGFR2 have shown no improvement in comparison to the free ligand. Besides, cytotoxicity assay on HepG2 cell line shows similar activity for complex and ligand in the range between 1–25 μM supporting the data obtained from studies in solution.


2021 ◽  
Author(s):  
Abhinav Parashar ◽  
Kelath Murali Manoj

Using in silico docking approaches, we scan the various subunits of Complex V (FoF1ATPase) for putative adenosine nucleotide binding sites. We find that multiple generic ADP/ATP binding sites are present on the alpha-beta binding sites and a conserved ATP binding site is present on the epsilon subunit. These findings support the murburn model of Complex V.


2021 ◽  
Vol 14 (12) ◽  
pp. 1290
Author(s):  
Karishma K. Mashelkar ◽  
Woong Sub Byun ◽  
Hyejin Ko ◽  
Kisu Sung ◽  
Sushil K. Tripathi ◽  
...  

The development of anticancer drugs remains challenging owing to the potential for drug resistance. The simultaneous inhibition of multiple targets involved in cancer could overcome resistance, and these agents would exhibit higher potency than single-target inhibitors. Protein kinases represent a promising target for the development of anticancer agents. As most multi-kinase inhibitors are heterocycles occupying only the hinge and hydrophobic region in the ATP binding site, we aimed to design multi-kinase inhibitors that would occupy the ribose pocket, along with the hinge and hydrophobic region, based on ATP-kinase interactions. Herein, we report the discovery of a novel 4′-thionucleoside template as a multi-kinase inhibitor with potent anticancer activity. The in vitro evaluation revealed a lead 1g (7-acetylene-7-deaza-4′-thioadenosine) with potent anticancer activity, and marked inhibition of TRKA, CK1δ, and DYRK1A/1B kinases in the kinome scan assay. We believe that these findings will pave the way for developing anticancer drugs.


Author(s):  
Setsu Nakae ◽  
Maho Kitamura ◽  
Daisuke Fujiwara ◽  
Masaaki Sawa ◽  
Tsuyoshi Shirai ◽  
...  

Eukaryotic protein kinases contain an Asp-Phe-Gly (DFG) motif, the conformation of which is involved in controlling the catalytic activity, at the N-terminus of the activation segment. The motif can be switched between active-state (DFG-in) and inactive-state (DFG-out) conformations: however, the mechanism of conformational change is poorly understood, partly because there are few reports of the DFG-out conformation. Here, a novel crystal structure of nonphosphorylated human mitogen-activated protein kinase kinase 1 (MEK1; amino acids 38–381) complexed with ATP-γS is reported in which MEK1 adopts the DFG-out conformation. The crystal structure revealed that the structural elements (the αC helix and HRD motif) surrounding the active site are involved in the formation/stabilization of the DFG-out conformation. The ATP-γS molecule was bound to the canonical ATP-binding site in a different binding mode that has never been found in previously determined crystal structures of MEK1. This novel ATP-γS binding mode provides a starting point for the design of high-affinity inhibitors of nonphosphorylated inactive MEK1 that adopts the DFG-out conformation.


2021 ◽  
Vol 118 (48) ◽  
pp. e2112267118
Author(s):  
Chen Zhao ◽  
Roderick MacKinnon

KATP channels are metabolic sensors that translate intracellular ATP/ADP balance into membrane excitability. The molecular composition of KATP includes an inward-rectifier potassium channel (Kir) and an ABC transporter–like sulfonylurea receptor (SUR). Although structures of KATP have been determined in many conformations, in all cases, the pore in Kir is closed. Here, we describe human pancreatic KATP (hKATP) structures with an open pore at 3.1- to 4.0-Å resolution using single-particle cryo-electron microscopy (cryo-EM). Pore opening is associated with coordinated structural changes within the ATP-binding site and the channel gate in Kir. Conformational changes in SUR are also observed, resulting in an area reduction of contact surfaces between SUR and Kir. We also observe that pancreatic hKATP exhibits the unique (among inward-rectifier channels) property of PIP2-independent opening, which appears to be correlated with a docked cytoplasmic domain in the absence of PIP2.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Elodie Mareux ◽  
Martine Lapalus ◽  
Amel Ben-Saad ◽  
Isabelle Callebaut ◽  
Thomas Falguières ◽  
...  

Abstract Background ABCB11 variations are responsible for a spectrum of rare liver diseases, including progressive familial intrahepatic cholestasis type 2 (PFIC2) and intrahepatic cholestasis of pregnancy (ICP). Current medical treatment of these conditions mostly relies on ursodeoxycholic acid with limited efficacy. We report on the in vitro study of the p.A257V missense variant of ABCB11 identified in a PFIC2 patient and in her mother who experienced ICP. Results The Ala257 residue is located outside the ATP-binding site of ABCB11. We show that the p.A257V variant of ABCB11 is correctly expressed at the canalicular membrane of HepG2 cells but that its function significantly decreased when studied in MDCK cells. This functional defect can be fully rescued by Ivacaftor. Conclusion Ivacaftor could be considered as a new pharmacological tool able to respond to an unmet medical need for patients with ICP and PFIC2 due to ABCB11 variations affecting ABCB11 function, even when the residue involved is not located in an ATP-binding site of ABCB11.


2021 ◽  
Vol 22 (19) ◽  
pp. 10670
Author(s):  
Fabian Freisleben ◽  
Franziska Modemann ◽  
Jana Muschhammer ◽  
Hauke Stamm ◽  
Franziska Brauneck ◽  
...  

The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.


2021 ◽  
Author(s):  
Walter Fiedler ◽  
Fabian Freisleben ◽  
Jasmin Wellbrock ◽  
Karl Kirschner

Recent experimental evidence suggest that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibit acute myeloid leukemia cell growth. In this study we use quantum mechanics (QM), molecular similarity and molecular dynamics (MD) calculations to predict possible binding poses of mebendazole to the adenosine triphosphate (ATP) binding site of Hsp90. Extensive conformational searches and minimization of the five tautomers of mebendazole using MP2/aug-cc-pVTZ theory level resulting in 152 minima being identified. Mebendazole-Hsp90 complex models were created using the QM optimized conformations and protein coordinates obtained from experimental crystal structures that were chosen through similarity calculations. Nine different poses were identified from a total of 600 ns of explicit solvent, all-atom MD simulations using two different force fields. All simulations support the hypothesis that mebendazole is able to bind to the ATP binding site of Hsp90.


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