binding mechanism
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Author(s):  
Yaocheng Wang ◽  
Xuelei Jiang ◽  
Zhenhao Zhong ◽  
Zhicheng Liu ◽  
Weiwen Li ◽  
...  
Keyword(s):  


2022 ◽  
pp. 132366
Author(s):  
Edina H. Avdović ◽  
Žiko B. Milanović ◽  
Krešimir Molčanov ◽  
Sunčica Roca ◽  
Dražen Vikić-Topić ◽  
...  


Chemosphere ◽  
2022 ◽  
pp. 133550
Author(s):  
Prashant Bhardwaj ◽  
G.P. Biswas ◽  
Nibedita Mahata ◽  
Susanta Ghanta ◽  
Biswanath Bhunia


2021 ◽  
Author(s):  
Bing Xie ◽  
Alexander Goldberg ◽  
Lei Shi

Fentanyl and its analogs are selective agonists of the µ-opioid receptor (MOR). Among novel synthetic opioids (NSOs), they dominate the recreational drug market and are the main culprits for the opioid crisis, which has been exacerbated by the COVID-19 pandemic. By taking advantage of the crystal structures of the MOR, several groups have investigated the binding mechanism of fentanyl, but have not reached a consensus, in terms of both the binding orientation and the fentanyl conformation. Thus, the binding mechanism of fentanyl at the MOR remains an unsolved and challenging question. Here, we carried out a systematic computational study to investigate the preferred fentanyl conformations, and how these conformations are being accommodated in the MOR binding pocket. We characterized the free energy landscape of fentanyl conformations with metadynamics simulations, as well as performed long-timescale molecular dynamics simulations to compare and evaluate several possible fentanyl binding conditions. Our results indicate that the most preferred binding pose in the MOR binding pocket corresponds well with the minima on the energy landscape of fentanyl in the absence of the receptor, while the energy landscape can be reconfigured by modifying the fentanyl scaffold. The interactions with the receptor may stabilize a slightly unfavored fentanyl conformation in an alternative binding pose. By extending similar investigations to fentanyl analogs, our findings establish a structure-activity relationship of fentanyl binding at the MOR. In addition to providing a structural basis to understand the potential toxicity of the emerging NSOs, such insights will contribute to developing new, safer analgesics.



2021 ◽  
Author(s):  
Zaira Rehman ◽  
Massab Umair ◽  
Aamer Ikram ◽  
Muhammad Salman ◽  
Syed Adnan Haider ◽  
...  

The emergence of SARS-CoV-2 omicron variant in late November, 2021 and its rapid spread to different countries, warns the health authorities to take initiative to work on containing its spread. The omicron SARS-CoV-2 variant is unusual from the other variants of concerns reported earlier as it harbors many novel mutations in its genome particularly with >30 mutations in the spike glycoprotein alone. The current study investigated the variation in binding mechanism which it carries compared to the wild type. The study also explored the interaction profile of spike-omicron with human ACE2 receptor. The structure of omicron spike glycoprotein was determined though homology modeling. The interaction analysis was performed through docking using HADDOCK followed by binding affinity calculation. Finally, the comparison of interactions were performed among spike-ACE2 complex of wild type, delta and omicron variants. The interaction analysis has revealed the involvement of highly charged and polar residues (H505, Arg498, Ser446, Arg493, and Tyr501) in the interactions. The important novel interactions in the spike-ACE2-omicron complex was observed as S494:H34, S496:D38, R498:Y41, Y501:K353, and H505:R393 and R493:D38. Moreover, the binding affinity of spike-ACE2-omicron complex (-17.6Kcal/mol) is much higher than wild type-ACE2 (-13.2Kcal/mol) and delta-ACE2 complex (-13.3Kcal/mol). These results indicate that the involvement of polar and charged residues in the interactions with ACE2 may have an impact on increased transmissibility of omicron variant.



2021 ◽  
Author(s):  
Carlos Moreno-Yruela ◽  
Christian Adam Olsen

Histone deacetylases (HDACs) 1-3 regulate chromatin structure and gene expression. These three enzymes are targets for cancer chemotherapy and are studied for the treatment of immune disorders and neurodegeneration, but there is a lack of selective pharmacological tool compounds to unravel their individual roles. Potent inhibitors of HDACs 1-3 often display slow-binding kinetics, which causes a delay in inhibitor-enzyme equilibration and may affect assay readout. Here, we compare the potency and selectivity of slow-binding inhibitors measured by discontinuous and continuous assays. We find that entinostat, a clinical candidate, inhibits HDACs 1-3 by a two-step, slow-binding mechanism with lower potencies than previously reported. In addition, we show that RGFP966, commercialized as HDAC3-selective probe, is a slow-binding inhibitor with inhibitor constants of 57 nM, 31 nM, and 13 nM against HDACs 1-3, respectively. These data highlight a need for thorough kinetic investigation in the development of selective HDAC probes.



Author(s):  
Jianli Liu ◽  
Jiahe Chen ◽  
Xiangyang Liu ◽  
Wei Shao ◽  
Xueying Mei ◽  
...  


mBio ◽  
2021 ◽  
Author(s):  
Todd A. Cameron ◽  
Daniel E. Vega ◽  
Chenfei Yu ◽  
Han Xiao ◽  
William Margolin

The tubulin homolog FtsZ plays a central early role in organizing bacterial cell division proteins at the cytoplasmic membrane. However, FtsZ does not directly interact with the membrane itself, instead relying on proteins such as FtsA to tether it to the membrane.



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