Inhibitor Binding to Hsp90: A Review of Thermodynamic, Kinetic, Enzymatic, and Cellular Assays

2014 ◽  
Vol 15 (3) ◽  
pp. 256-282 ◽  
Author(s):  
Vilma Petrikaite ◽  
Daumantas Matulis
2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Analise C. Doney ◽  
Steven Wheeler

<p>Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous <i>ab initio</i> data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.</p>


2019 ◽  
Vol 25 (42) ◽  
pp. 5803-5821 ◽  
Author(s):  
Mona N. Rahman ◽  
Dragic Vukomanovic ◽  
Jason Z. Vlahakis ◽  
Walter A. Szarek ◽  
Kanji Nakatsu ◽  
...  

The development of isozyme-selective heme oxygenase (HO) inhibitors promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties with a role in several disease states; thus, it is an enticing therapeutic target. Historically, the metalloporphyrins have been used as competitive HO inhibitors based on their structural similarity to the substrate, heme. However, heme’s important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), results in non-selectivity being an unfortunate side effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort over a decade ago to develop novel compounds as potent, selective inhibitors of HO. The result was the creation of the first generation of non-porphyrin based, non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated and provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. Notably, HO-1 inhibitors are of particular interest for the treatment of hyperbilirubinemia and certain types of cancer. Key features based on this initial study have already been used by others to discover additional potential HO-1 inhibitors. Moreover, studies have begun to use selected compounds and determine their effects in some disease models.


2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.


Author(s):  
Mingliang Fan ◽  
Jiping Li

Background: The combination of two or more therapeutic drugs is an attractive approach to improve the treatment of experimental tumors. Leveraging nanocarriers for combinational drug delivery can allow a control over drug biological fate and promote co-localization in the same area of the body. However, there are certain concerns regarding the biodegradability and potential long-term toxicity arising from these synthetic nanoscale carriers. Objective: Our aim was to develop a combinational nanodrug delivery system formed by self-assembling of amphiphilic drug molecules,minimizing potential toxicities associated with using additional synthetic nanocarriers. Methods: A novel prodrug chlorambucil gemcitabine conjugate was synthesized, this prodrug was used for the encapsulation of an additional hydrophobic anticancer drug paclitaxel, taking the form of combinational nanodrugs. Particle size and zeta potential were evaluated, cytotoxicity assay and apoptosis/cell cycle analysis were also performed to validate the anticancer efficacy of the combinational nanodrugs. Results: The combinational nanodrugs were acquired by means of nanoprecipitation. In A549 lung adenocarcinoma cell line, cellular assays revealed that co-delivery of low dosage paclitaxel with chlorambucil gemcitabine conjugate can act synergistically to inhibit cell growth and induce accumulation of cells in the G2/M phase with a concomitant decrease in G0/G1 compartment. Conclusion: Chlorambucil gemcitabine conjugate and paclitaxel can co-assemble into composite nanoparticles by a nanoprecipitation process and the resulting combinational nanodrugs showed synergistic anticancer effect. This synthetic nanocarrier-free approach might broaden the nanodrug concept and have potential in cancer therapy.


1987 ◽  
Vol 42 (6) ◽  
pp. 684-689 ◽  
Author(s):  
John L. Huppatz ◽  
John N. Phillips

Optically active α-methylbenzylamino 2-cyanoacrylic esters were synthesized and assayed as inhibitors of the Hill reaction in isolated pea chloroplast fragments. The 5-isomers were more potent inhibitors than the S-isomers with discriminations of from ten to greater than 100-fold being observed. A β-alkyl substituent in the cyanoacrylate molecule affected both the level of activity and the difference in activity between the isomers. An α,α-dimethylbenzylamino derivative was also active at about the same level as the corresponding α-methylbenzylamino racemate. This result could be explained in terms of the orientation of the phenyl ring in the receptor site. Replacement of the α-methylbenzylamino group by other α-alkyl and α-phenyl substituents had little effect on activity. However, an α-benzyl group was beneficial.


2020 ◽  
Vol 18 (16) ◽  
pp. 3069-3081 ◽  
Author(s):  
Maria G. Khrenova ◽  
Anna M. Kulakova ◽  
Alexander V. Nemukhin

Comprehensive molecular modeling and kinetic analysis reveal a novel mechanism of the inhibition of the oncogenic mutant of the “undruggable” KRAS protein.


mAbs ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 1954136
Author(s):  
Sujatha Kumar ◽  
Srimoyee Ghosh ◽  
Geeta Sharma ◽  
Zebin Wang ◽  
Marilyn R. Kehry ◽  
...  

2020 ◽  
Vol 35 (4) ◽  
pp. 461-470
Author(s):  
Huibin Guo ◽  
Lei Jin ◽  
Sijing Huang

AbstractThe health risks brought by particles cannot be present via a sole parameter. Instead, the particulate matter oxidative potential (PM OP), which expresses combined redox properties of particles, is used as an integrated metric to assess associated hazards and particle-induced health effects. OP definition provides the capacity of PM toward target oxidation. The latest technologies of a cellular OP measurement has been growing in relevant studies. In this review, OP measurement techniques are focused on discussing along with PM characterization because of many related studies via OP measurements investigating relationship with human health. Many OP measurement methods, such as dithiothreitol (DTT), ascorbic acid (AA), glutathione (GSH) assay and other a cellular assays, are used to study the association between PM toxicity and PM characterization that make different responses, including PM components, size and sources. Briefly, AA and DTT assays are sensitive to metals (such as copper, manganese and iron etc.) and organics (quinones, VOCs and PAH). Measured OP have significant association with certain PM-related end points, for example, lung cancer, COPD and asthma. Literature has found that exposure to measured OP has higher risk ratios than sole PM mass, which may be containing the PM health-relevant fraction. PM characterization effect on health via OP measurement display a promising method.


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