Molecules which bind to proteins that aggregate abnormally in neurodegenerative diseases could be promising drugs for these diseases. In this study, Zhang, Wu, Zhang, and Dang simulate the binding behavior of various molecules to screen for candidates which could be promising candidates for drug development.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors that bind to the HIV reverse transcriptase and prevent replication. Indolyl aryl sulfones (IAS) and IAS derivatives have been found to be highly effective against mutant strains of HIV-1 reverse transcriptase. Here, we analyzed molecules designed using aryl sulfone scaffolds paired to cyclic compounds as potential NNRTIs through the computational design and docking of 100 novel NNRTI candidates. Moreover, we explored the specific combinations of functional groups and aryl sulfones that resulted in the NNRTI candidates with the strongest binding affinity while testing all compounds for carcinogenicity. We hypothesized that the combination of an IAS scaffold and pyrimidine would produce the compounds with the best binding affinity. Our hypothesis was correct as the series of molecules with an IAS scaffold and pyrimidine exhibited the best average binding affinity. Additionally, this study found 32 molecules designed in this procedure with higher or equal binding affinities to the previously successful IAS derivative 5-bromo-3-[(3,5-dimethylphenyl)sulfonyl]indole-2-carboxyamide when docked to HIV-1 reverse transcriptase.
The Wnt signaling pathway, known to coordinate important aspects of cellular homeostasis ranging from differentiation, proliferation, migration, and much more, is dysregulated in many human diseases. This study demonstrates that aminomethylphosphonic acid, which is the main metabolite found in the common herbicide Glyphosate, is toxic to planaria and capable of binding to canonical Wnt proteins.
In order for cells to successfully multiply, a number of proteins are needed to correctly coordinate the replication and division process. In this study, students use fluorescence microscopy and molecular methods to study CCDC11, a protein critical in the formation of cilia. Interestingly, they uncover a new role for CCDC11, critical in the cell division across multiple human cell lines.
Here, seeking to better understand the roles of glycans in the receptors of active sites of neuronal cells, the authors used molecular dynamics simulations to to uncover the dynamic nature of N-glycans on membrane proteins. The authors suggest the study of theinteractions of these membrane poreins could provide future potential therapeutic targets to treat mental diseases.
In an extensive study of gene mutations, and their resulting effect on protein-protein interactions, Desai and Stork found that HTT-PRPF40B-MECP2 interactions are weakened with progression of Lopes-Maciel-Rodan syndrome.
Berberine, a natural product alkaloid, and its analogs have a wide range of medicinal properties, including antibacterial and anticancer effects. Here, the authors explored a library of alkyl or aryl berberine analogs to probe binding to double-stranded and G-quadruplex DNA. They determined that the nature of the substituent, the position of the substituent, and the nucleic acid target affect the free energy of binding of berberine analogs to DNA and G-quadruplex DNA, however berberine analogs did not result in net stabilization of G-quadruplex DNA.
In this study, the authors looked at a proto-oncogene, KRAS, and searched for molecules that are predicted to be able to bind to the inactive form of KRAS. They found that a modified version of Irbesartan, a derivative of benzimidazole, showed the best binding to inactive KRAS.
Anticholinergics are used in treating asthma, a chronic inflammation of the airways. These drugs block human M1 and M2 muscarinic acetylcholine receptors, inhibiting bronchoconstriction. However, studies have reported complications of anticholinergic usage, such as exacerbated eosinophil production and worsened urinary retention. Modification of known anticholinergics using bioisosteric replacements to increase efficacy could potentially minimize these complications. The present study focuses on identifying viable analogs of anticholinergics to improve binding energy to the receptors compared to current treatment options. Glycopyrrolate (G), ipratropium (IB), and tiotropium bromide (TB) were chosen as parent drugs of interest, due to the presence of common functional groups within the molecules, specifically esters and alcohols. Docking score analysis via AutoDock Vina was used to evaluate the binding energy between drug analogs and the muscarinic acetylcholine receptors. The final results suggest that G-A3, IB-A3, and TB-A1 are the most viable analogs, as binding energy was improved when compared to the parent drug. G-A4, IB-A4, IB-A5, TB-A3, and TB-A4 are also potential candidates, although there were slight regressions in binding energy to both muscarinic receptors for these analogs. By researching the effects of bioisosteric replacements of current anticholinergics, it is evident that there is a potential to provide asthmatics with more effective treatment options.
With advancements in machine learning a large data scale, high throughput virtual screening has become a more attractive method for screening drug candidates. This study compared the accuracy of molecular descriptors from two cheminformatics Mordred and PaDEL, software libraries, in characterizing the chemo-structural composition of 53 compounds from the non-nucleoside reverse transcriptase inhibitors (NNRTI) class. The classification model built with the filtered set of descriptors from Mordred was superior to the model using PaDEL descriptors. This approach can accelerate the identification of hit compounds and improve the efficiency of the drug discovery pipeline.