Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: Protein structure-guided design and SAR

Richardson, Christine M.; Williamson, D.S.; Parratt, Martin J.; Borgognoni, Jenifer; Cansfield, Andrew D.; Dokurno, P.; Francis, Geraint L.; Howes, Rob; Moore, Jonathan D.; Murray, James B.; Robertson, Alan; Surgenor, A.E.; Torrance, C

doi:10.1016/j.bmcl.2005.11.048

Cited by 68 publications

(51 citation statements)

References 19 publications

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“…There are, however, some structures strictly representing the concept of orthogonal halogen bonds to π-electrons of the amide group, originally identified by Voth (Voth et al, 2009). In the complex of human CDK2 with a brominated triazole-pyrimidine inhibitor (pdb2c69; Richardson et al, 2006), the separate X-bond to the backbone nitrogen of Glu12 could be identified ( Fig. 2A), while in the complex of epidermal growth factor receptor variant with PD168393 (pdb4lrm; Yasuda et al, 2013), the bromine atom makes numerous short orthogonal contacts with X-bond acceptors located in the proximal β-sheets ( Fig.…”

Section: Below)mentioning

confidence: 99%

Halogen bonds involved in binding of halogenated ligands by protein kinases.

et al. 2016

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Analysis of 664 known structures of protein kinase complexes with halogenated ligands revealed 424 short contacts between a halogen atom and a potential protein X-bond acceptor, the topology and geometry of which were analyzed according to the type of a halogen atom (X = Cl, Br, I) and a putative protein X-bond acceptor. Among 236 identified halogen bonds, the most represented ones are directed to backbone carbonyls of the hinge region and may replace the pattern of ATP-like hydrogen bonds. Some halogen-π interactions with either aromatic residues or peptide bonds, that accompany the interaction with the hinge region, may possibly enhance ligand selectivity. Interestingly, many of these halogen-π interactions are bifurcated. Geometrical preferences identify iodine as the strongest X-bond donor, less so bromine, while virtually no such preferences were observed for chlorine; and a backbone carbonyl as the strongest X-bond acceptor. The presence of a halogen atom in a ligand additionally affects the properties of proximal hydrogen bonds, which according to geometrical parameters get strengthened, when a nitrogen of a halogenated ligand acts as the hydrogen bond donor.

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Section: Below)mentioning

confidence: 99%

Halogen bonds involved in binding of halogenated ligands by protein kinases.

et al. 2016

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“…A group at Vernalis studied triazolopyrimidine derivatives as inhibitors of CDK2. 81 They report the complex structures of the same inhibitor NU6102 with monomeric CDK2 and with the CDK2/cyclin A complex. Both structures are deposited in the PDB and depicted in Figure 14.…”

Section: Substituted Aryl Systems -Stereoelectronic and Steric Effectsmentioning

confidence: 99%

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Brameld

Kuhn

Reuter

et al. 2008

J. Chem. Inf. Model.

340

332

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Based on torsion angle distributions of frequently occurring substructures, conformation preferences of druglike molecules are presented, accompanied by a review of the relevant literature. First, the relevance of the Cambridge Structural Database (CSD) for drug design is demonstrated by comparing substructures present in compounds entering clinical trials with those found in the CSD and protein-bound ligands in the Protein Data Bank (PDB). Next, we briefly highlight preferred conformations of elementary acyclic systems, followed by a discussion of sulfonamide conformations. Due to their central role in medicinal chemistry, we discuss properties of aryl ring substituents in depth, including biaryl systems and systems of two aryl rings connected by two acyclic bonds. For a subset of torsion motifs, we also compare torsion angle histograms derived from CSD structures with those derived from ligands in the PDB. Furthermore, selected properties of some six-and seven-membered ring systems are discussed. The article closes with a section on attractive sulfuroxygen contacts.

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“…Therefore, the binding modes between the isomers of Wangzaozin A and CDK2 are investigated. After stabilizing the structure by MD, the active site docked by X (red stick structure) and X 0 (blue stick structure) in Figure 3 is identical to Ref 35 (Supplement Figure S1). In the active site, a 3.125-Å H bond links the oxygen atom of glutamine 125 and O2 of X.…”

Section: Wangzaozin a Induces Apoptosismentioning

confidence: 81%

Study on Wangzaozin-A-Inducing Cancer Apoptosis and Its Theoretical Protein Targets

Chen

Wang

2016

Technol Cancer Res Treat

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Wangzaozin A is the most representative cytotoxic C-20-nonoxide compound of Isodon plants of Labiatae. The protein targets of the 2 isomers (X and X 0 ) of Wangzaozin A are, respectively, extracted from target fishing dock Web site. Each isomer has 23 targets with good energy scores. The binding modes of each isomer and its targets are, respectively, analyzed by Dock. The energy score of the binding mode between the isomer X and the inositol-1(or 4)-monophosphatase is the smallest. The apoptosis, antiproliferative, and lethal effects of human gastric cancer cells induced by Wangzaozin A are assessed by trypan blue exclusion, hoechst33258 stain in SGC-7901, and flow cytometric measurement. The mechanism of Wangzaozin-A-inducing cancer apoptosis is analyzed. Wangzaozin A inhibits the growth of human gastric cancer SGC-7901 cell lines at the lower concentration (<4.0 mmol/L) and results in the lethal effect at the relative higher concentration (>8.0 mmol/L).

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Triazolo[1,5-a]pyrimidines as novel CDK2 inhibitors: Protein structure-guided design and SAR

Cited by 68 publications

References 19 publications

Halogen bonds involved in binding of halogenated ligands by protein kinases.

Halogen bonds involved in binding of halogenated ligands by protein kinases.

Small Molecule Conformational Preferences Derived from Crystal Structure Data. A Medicinal Chemistry Focused Analysis

Study on Wangzaozin-A-Inducing Cancer Apoptosis and Its Theoretical Protein Targets

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