Study of novel pyrazolo[3,4-d]pyrimidine derivatives as selective TgCDPK1 inhibitors: molecular docking, structure-based 3D-QSAR and molecular dynamics simulation

Ma, Shaojie; Zhou, Shengfu; Lin, Weicong; Zhang, Rong; Wu, Wenjuan; Zheng, Kang‐Cheng

doi:10.1039/c6ra20277b

Cited by 4 publications

(3 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The libraries of drug-like compounds used in this screening study were provided by LifeArc [40]. Similar compounds to those identified in this study have been reported as inhibitors of various kinases [47][48][49][50][51][52][53] and also of bacterial cell-wall biosynthetic enzymes which use UDP derivatives as substrates [54]. However, this appears to be the first report of such compounds inhibiting an enzyme using an acyl-CoA substrate.…”

Section: Discussionsupporting

confidence: 67%

Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships

Petrova

Wadda

Nathubhai

et al. 2019

Bioorganic Chemistry

View full text Add to dashboard Cite

α-Methylacyl-CoA racemase (AMACR; P504S; EC 5.1.99.4) catalyses epimerization of 2-methylacyl-CoAs and is important for the degradation of branched-chain fatty acids and the pharmacological activation of ibuprofen and related drugs. It is also a novel drug target for prostate and other cancers. However, development of AMACR as a drug target has been hampered by the difficulties in assaying enzyme activity. Consequently, reported inhibitors have been rationally designed acyl-CoA esters, which are delivered as their carboxylate prodrugs. The novel colorimetric assay for AMACR based on the elimination of 2,4-dinitrophenolate was developed for high-throughput screening and 20,387 'drug-like compounds' were screened, with a throughput of 768 compounds assayed per day. Pyrazoloquinolines and pyrazolopyrimidines were identified as novel scaffolds and investigated as AMACR inhibitors. The most potent inhibitors have IC50 values of ~2 µM. The pyrazoloquinoline inhibitor 10a displayed uncompetitive inhibition, whilst 10j displayed mixed competitive inhibition. The pyrazolopyr-imidine inhibitor 11k displayed uncompetitive inhibition. This is the first report of the identification of specific drug-like small-molecule AMACR inhibitors by high-throughput screening. Pyrazoloquinolines and pyr-azolopyrimidines may also be useful as inhibitors of other CoA-utilizing enzymes.

show abstract

Section: Discussionsupporting

confidence: 67%

Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships

Petrova

Wadda

Nathubhai

et al. 2019

Bioorganic Chemistry

View full text Add to dashboard Cite

show abstract

“…A wide range of pharmacological properties such as anti-inflammatory and analgesic (Kadry 2014), anti-tubercular (Trivedi et al 2012) antitumor and antiparasitic (Kandeel et al 2013;Ma et al 2016) and herbicidal activities (Liu et al 2007) were also described in the literatures.…”

Section: Introductionmentioning

confidence: 98%

Synthesis and in vitro antibacterial evaluation of 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidines

et al. 2017

View full text Add to dashboard Cite

Pyrazolo[3,pyrimidines are one of the most important classes of fused heterocyclic compounds which exhibit a broad range of biological and medicinal properties. They are known as anticancer, antifungal, antibacterial, antiviral and anti-inflammatory agents. In this study, some new 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidine derivatives were prepared via reaction of 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carbonitrile with various nitriles in the presence of sodium ethoxide as catalyst. The inhibitory properties of synthesized compounds were studied according to CLSI guidelines against some pathogenic bacteria including four gram-positive strains (Streptococcus pyogenes, Staphylococcus aureus, Bacillus cereus and Bacillus subtilis subsp. spizizenii) and three gramnegative strains (Pseudomonas aeruginosa, Shigella flexneri and Salmonella enterica subsp. enterica). The antibacterial effects of all derivatives were compared with those of antibiotics belonging to different classes. The values were reported as inhibition zone diameter (IZD), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The effect of substituents on the biological activity of derivatives was discussed as well. The inhibitory effect of compound 6a, was shown to be the most, with MIC values in the range of 32-4096 lg/mL. Since most of the synthesized compounds were effective against Streptococcus pyogenes and Pseudomonas aeruginosa, they can be considered as inhibitors of these two bacteria.

show abstract

“…28 Ma et al analyzed pyrazolo [3,4-d]pyrimidine derivatives as the TgCDPK1 inhibitors using the 3D-QSAR, docking, dynamics simulation, and then designed some new inhibitors. 29 Therefore, the application of CADD methods into the research of LSD1 inhibitors should be efficient for designing new and highly active LSD1 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR, molecular docking, and molecular dynamics simulation study of thieno[3,2-b]pyrrole-5-carboxamide derivatives as LSD1 inhibitors

Liu

et al. 2020

RSC Adv.

View full text Add to dashboard Cite

show abstract

Study of novel pyrazolo[3,4-d]pyrimidine derivatives as selective TgCDPK1 inhibitors: molecular docking, structure-based 3D-QSAR and molecular dynamics simulation

Abstract: We explored the structural features that have an impact on TgCDPK1 activity and TgCDPK1/Src selectivity by multi-computational methods with different statistical models.

Cited by 4 publications

References 45 publications

Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships

Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure-activity relationships

Synthesis and in vitro antibacterial evaluation of 6-substituted 4-amino-pyrazolo[3,4-d]pyrimidines

3D-QSAR, molecular docking, and molecular dynamics simulation study of thieno[3,2-b]pyrrole-5-carboxamide derivatives as LSD1 inhibitors

Contact Info

Product

Resources

About