Synthesis of 4‐(2‐Phenylhydrazono)‐1‐(4‐phenylthiazol‐2‐yl)‐1<i>H</i>‐pyrazol‐5(4<i>H</i>)‐one Compounds and Characterization of Their Affinities to Anti‐apoptotic Bcl‐2 Family Proteins

Shi, Shicheng; Han, Lingli; Zhou, Mi; Li, Yangfeng; Liu, Zhen; Yu, Biao; Wang, Renxiao

doi:10.1002/cjoc.201300426

Cited by 2 publications

(1 citation statement)

References 30 publications

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“…Their molecular structures were sketched by using the Schrodinger software (version 2017−1). 56 It should be noted that, according to the reported crystal structures of BAM7 57 and BTSA1, 58 the C�N double bond in these two molecules is in the Z configuration due to formation of an intramolecular H bond. In addition, predicted pK a values for all titratable groups on these three molecules indicate that those groups are expected to remain in their neutral form under physiological pH conditions (see Table S3 in the Supporting Information).…”

Section: Cosolvent MD Simulationmentioning

confidence: 99%

Analysis of the Binding Sites on BAX and the Mechanism of BAX Activators through Extensive Molecular Dynamics Simulations

Feng

Zhang

et al. 2021

J. Chem. Inf. Model.

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The BAX protein is a pro-apoptotic member of the Bcl-2 family, which triggers apoptosis by causing permeabilization of the mitochondrial outer membrane. However, the activation mechanism of BAX is far from being understood. Although a few small-molecule BAX activators have been reported in the literature, their crystal structures in complex with BAX have not been resolved. So far, their binding modes were modeled at most by simple molecular docking efforts. Lack of an in-depth understanding of the activation mechanism of BAX hinders the development of more effective BAX activators. In this work, we employed cosolvent molecular dynamics simulation to detect the potential binding sites on the surface of BAX and performed a long-time molecular dynamics simulation (50 μs in total) to derive the possible binding modes of three BAX activators (i.e., BAM7, BTC-8, and BTSA1) reported in the literature. Our results indicate that the trigger, S184, and vMIA sites are the three major binding sites on the full-length BAX structure. Moreover, the canonical hydrophobic groove is clearly detected on the α9-truncated BAX structure, which is consistent with the outcomes of relevant experimental studies. Interestingly, it is observed that solvent probes bind to the trigger bottom pocket more stably than the PPI trigger site. Each activator was subjected to unbiased molecular dynamics simulations started at the three major binding sites in five parallel jobs. Our MD results indicate that all three activators tend to stay at the trigger site with favorable MM-GB/SA binding energies. BAM7 and BTSA1 can enter the trigger bottom pocket and thereby enhance the movement of the α1−α2 loop, which may be a key factor at the early stage of BAX activation. Our molecular modeling results may provide useful guidance for designing smart biological experiments to further explore BAX activation and directing structure-based efforts toward discovering more effective BAX activators.

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Section: Cosolvent MD Simulationmentioning

confidence: 99%

Analysis of the Binding Sites on BAX and the Mechanism of BAX Activators through Extensive Molecular Dynamics Simulations

Feng

Zhang

et al. 2021

J. Chem. Inf. Model.

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Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry

Dogo‐Isonagie

Su-Lin

Lohith

et al. 2016

Bioorganic & Medicinal Chemistry

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In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N-terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and tri-sulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus.

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Synthesis of 4‐(2‐Phenylhydrazono)‐1‐(4‐phenylthiazol‐2‐yl)‐1H‐pyrazol‐5(4H)‐one Compounds and Characterization of Their Affinities to Anti‐apoptotic Bcl‐2 Family Proteins

Cited by 2 publications

References 30 publications

Analysis of the Binding Sites on BAX and the Mechanism of BAX Activators through Extensive Molecular Dynamics Simulations

Analysis of the Binding Sites on BAX and the Mechanism of BAX Activators through Extensive Molecular Dynamics Simulations

Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry

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