Molecular docking study, synthesis and biological evaluation of Mannich bases as Hsp90 inhibitors

Gupta, Sayan Dutta; Bommaka, Manish Kumar; Mazaira, Gisela Ileana; Galigniana, Mario D.; Subrahmanyam, C. V. S.; Gowrishankar, N. L.; Raghavendra, Narasimha

doi:10.1016/j.ijbiomac.2015.06.039

Cited by 12 publications

(4 citation statements)

References 44 publications

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“…To predict the potential binding targets of compounds (±)- 1 and (±)- 2 and illustrate the accurate binding model and mechanism of interaction, molecular docking analyses were performed with Surflex-Dock as implemented in the SYBYL-X 2.0 program package (Tripos International, St. Louis, MO, USA)2122. The crystal structures of the docking targets including KSHV protease, KSHV LANA, PKC, P38, JNK, and ERK were obtained from the Protein Data Bank (http://www.rcsb.org)232425262728.…”

Section: Methodsmentioning

confidence: 99%

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

Zhu

et al. 2016

Sci Rep

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Two pairs of new enantiomers with unusual 5,5-spiroketal cores, termed (±)-japonones A and B [(±)-1 and (±)-2], were obtained from Hypericum japonicum Thunb. The absolute configurations of (±)-1 and (±)-2 were characterized by extensive analyses of spectroscopic data and calculated electronic circular dichroism (ECD) spectra, the application of modified Mosher’s methods, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Among these metabolites, (+)-1 exhibited some inhibitory activity on Kaposi’s sarcoma associated herpesvirus (KSHV). Virtual screening of (±)-1 and (±)-2 were conducted using the Surflex-Dock module in the Sybyl software, and (+)-1 exhibited ability to bind with ERK to form key interactions with residues Lys52, Pro56, Ile101, Asp165, Gly167 and Val99.

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Section: Methodsmentioning

confidence: 99%

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

Zhu

et al. 2016

Sci Rep

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“…The total score of molecular docking which predicted by software represented the binding affinity between protein and drug, and the score was expressed as binding constant, pKd [13]. A high value of total score indicates a good affinity of the drug with protein.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the stability and affinity of BlaR-CTD protein to β-lactam antibiotics based on docking and mutagenesis studies

et al. 2019

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Owing to the thermal instability and low affinity of BlaR-CTD to some β-lactams, the receptor assay based on BlaR-CTD is limited in the detection of abundant variety of drugs and the result is often unstable. In this study, the three-dimensional structure of BlaR-CTD from Bacillus licheniformis ATCC14580 was constructed by homologous modeling based on the crystal structure of BlaR-CTD from B. licheniformis 749/I, and the binding sites of this protein to 40 β-lactams were also obtained by molecular docking. To improve the stability and affinity of the protein, 23 mutant proteins were designed based on docking and homologous alignment results as well as by inserting disulfide bond and building the salt bridge. The mutation was rationality evaluated by SIFT and PloyPhen2 software. The heterologous expressed and purified mutant proteins were then subjected to the activity and stability assay. It was shown that among all mutant proteins, I188K/S19C/G24C, A138E/R50C/Q147C and S190Y/E183C/I188K respectively exhibited a higher affinity to 33, 22 and 21 β-lactams than the wild-type protein, while I188K/S19C/G24C exhibited the best stability. This may due to that the conformation of the active site in mutant protein I188K/S19C/G24C changed, and the random coli in the surface of protein activity increased. Our study suggests a possible structure-function relationship on the stability and affinity of BlaR-CTD, which provides new insights into protein rational design study and lays a solid foundation for establishing the receptor-based screening assay for the detection of β-lactam residues. Electronic supplementary material The online version of this article (10.1186/s13036-019-0157-4) contains supplementary material, which is available to authorized users.

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“…The Surflex-Dock program was used for the docking calculations. The protomol threshold was set to 0.50 Å [ 53 ]. Ligands were rendered flexible in surflex docking routine.…”

Section: Methodsmentioning

confidence: 99%

Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity

Qiao

Deng

Liu

et al. 2023

Oxidative Medicine and Cellular Longevity

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Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions with no pharmacological treatment approved. Several highly accessible computational tools were employed to predict the activities of twelve novel compounds prior to actual chemical synthesis. We began our work by designing two or three hydroxyl groups appended to the phenyl ketone core, followed by prediction of drug-likeness and targets. Most predicted targets for each compound overlapped with NAFLD targets (≥80%). Enrichment analysis showed that these compounds might regulate oxidoreductase activity. Then, these compounds were synthesized and confirmed by IR, MS, 1H, and 13C NMR. Their cell viability demonstrated that twelve compounds exhibited appreciable potencies against NAFLD ( E C 50 values ≤ 13.5 μ M ). Furthermore, the most potent compound 5f effectively prevented NAFLD progression as evidenced by the change in histological features. 5f significantly reduced total cholesterol and triglyceride levels in vitro/in vivo, and the effects of 5f were significantly stronger than those of the control drug. The proteomic data showed that oxidoreductase activity was the most significantly enriched, and this finding was consistent with docking results. In summary, this validated presynthesis prediction approach was cost-saving and worthy of popularization. The novel synthetic phenyl ketone derivative 5f holds great therapeutic potential by modulating oxidoreductase activity to counter NAFLD.

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Molecular docking study, synthesis and biological evaluation of Mannich bases as Hsp90 inhibitors

Cited by 12 publications

References 44 publications

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

Analysis of the stability and affinity of BlaR-CTD protein to β-lactam antibiotics based on docking and mutagenesis studies

Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity

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