Author: Talele, Tanaji T ; Pathak, Sanjai Kumar ; Gobbooru, Shruthi ; Low, Woon-Kai ; Shao, Xuwei ; Subramaniam, Gopal ; Pak, Steven ; Velagapudi, Uday Kiran ; Kommaraju, Sai Shilpa

Poly(ADP-ribose) polymerase 1 (PARP1), a widely explored anticancer drug target, plays an important role in single-strand DNA break repair processes. High-throughput virtual screening (HTVS) of a Maybridge small molecule library using the PARP1-benzimidazole-4-carboxamide co-crystal structure and pharmacophore model led to the identification of eleven compounds. These compounds were evaluated using recombinant PARP1 enzyme assay that resulted in the acquisition of three PARP1 inhibitors: 3 (IC₅₀ = 12 μM), 4 (IC₅₀ = 5.8 μM), and 10 (IC₅₀ = 0.88 μM). Compound 4 (2,3-dihydro-1,4-benzodioxine-5-carboxamide) was selected as a lead and was subjected to further chemical modifications, involving analogue synthesis and scaffold hopping. These efforts led to the identification of (Z)-2-(4-hydroxybenzylidene)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxamide (49, IC₅₀ = 0.082 μM) as the most potent inhibitor of PARP1 from the series.

13 Nov 2014·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Discovery of Highly Potent Dual CysLT₁ and CysLT₂ Antagonist

Q3 · MEDICINE

Article

Author: Ima, Masaki ; Nakayama, Yoshisuke ; Takahashi, Shinya ; Takeuchi, Jun ; Fujita, Manabu ; Itadani, Satoshi ; Sekiguchi, Tetsuya

The benzoxazine derivative, (2S)-4-(3-carboxypropyl)-8-{[4-(4-phenylbutoxy)benzoyl]amino}-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (19, ONO-2050297), was identified as the first potent dual CysLT1 and CysLT2 antagonist with IC50 values of 0.017 μM (CysLT1) and 0.00087 μM (CysLT2), respectively.

01 Dec 2012·Journal of Biological ChemistryQ2 · BIOLOGY

Role of Conformational Dynamics in α-Amino-3-hydroxy-5-methylisoxazole-4-propionic Acid (AMPA) Receptor Partial Agonism

Q2 · BIOLOGY

Article

Author: Christy F. Landes ; Heui Uhm ; David M. MacLean ; Swarna Ramaswamy ; David Cooper ; Vasanthi Jayaraman ; Nitesh Poddar ; Anu Rambhadran ; J. Nick Taylor

We have investigated the range of cleft closure conformational states that the agonist-binding domains of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors occupy when bound to a series of willardiine derivatives using single-molecule FRET. These studies show that the agonist-binding domain exhibits varying degrees of dynamics when bound to the different willardiines with differing efficacies. The chlorowillardiine- and nitrowillardiine-bound form of the agonist-binding domain probes a narrower range of cleft closure states relative to the iodowillardiine bound form of the protein, with the antagonist (αS)-α-amino-3-[(4-carboxyphenyl)methyl]-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinepropanoic acid (UBP-282)-bound form exhibiting the widest range of cleft closure states. Additionally, the average cleft closure follows the order UBP-282 > iodowillardiine > chlorowillardiine > nitrowillardiine-bound forms of agonist-binding domain. These single-molecule FRET data, along with our previously reported data for the glutamate-bound forms of wild type and T686S mutant proteins, show that the mean currents under nondesensitizing conditions can be directly correlated to the fraction of the agonist-binding domains in the "closed" cleft conformation. These results indicate that channel opening in the AMPA receptors is controlled by both the ability of the agonist to induce cleft closure and the dynamics of the agonist-binding domain when bound to the agonist.

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