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Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 509
Author(s):  
Meirambek Ospanov ◽  
Suresh P. Sulochana ◽  
Jason J. Paris ◽  
John M. Rimoldi ◽  
Nicole Ashpole ◽  
...  

Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.


2022 ◽  
Vol 23 (2) ◽  
pp. 811
Author(s):  
Maiia E. Bragina ◽  
Antoine Daina ◽  
Marta A. S. Perez ◽  
Olivier Michielin ◽  
Vincent Zoete

Hit finding, scaffold hopping, and structure–activity relationship studies are important tasks in rational drug discovery. Implementation of these tasks strongly depends on the availability of compounds similar to a known bioactive molecule. SwissSimilarity is a web tool for low-to-high-throughput virtual screening of multiple chemical libraries to find molecules similar to a compound of interest. According to the similarity principle, the output list of molecules generated by SwissSimilarity is expected to be enriched in compounds that are likely to share common protein targets with the query molecule and that can, therefore, be acquired and tested experimentally in priority. Compound libraries available for screening using SwissSimilarity include approved drugs, clinical candidates, known bioactive molecules, commercially available and synthetically accessible compounds. The first version of SwissSimilarity launched in 2015 made use of various 2D and 3D molecular descriptors, including path-based FP2 fingerprints and ElectroShape vectors. However, during the last few years, new fingerprinting methods for molecular description have been developed or have become popular. Here we would like to announce the launch of the new version of the SwissSimilarity web tool, which features additional 2D and 3D methods for estimation of molecular similarity: extended-connectivity, MinHash, 2D pharmacophore, extended reduced graph, and extended 3D fingerprints. Moreover, it is now possible to screen for molecular structures having the same scaffold as the query compound. Additionally, all compound libraries available for screening in SwissSimilarity have been updated, and several new ones have been added to the list. Finally, the interface of the website has been comprehensively rebuilt to provide a better user experience. The new version of SwissSimilarity is freely available starting from December 2021.


2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Richie R. Bhandare ◽  
Bulti Bakchi ◽  
Dilep Kumar Sigalapalli ◽  
Afzal B. Shaik

Abstract VEGFR-2 enzyme known for physiological functioning of the cell also involves in pathological angiogenesis and tumor progression. Recently VEGFR-2 has gained the interest of researchers all around the world as a promising target for the drug design and discovery of new anticancer agents. VEGFR2 inhibitors are a major class of anticancer agents used for clinical purposes. In silico methods like virtual screening, molecular docking, molecular dynamics, pharmacophore modeling, and other computational approaches help extensively in identifying the main molecular interactions necessary for the binding of the small molecules with the respective protein target to obtain the expected pharmacological potency. In this chapter, we discussed some representative case studies of in silico techniques used to determine molecular interactions and rational drug design of VEGFR-2 inhibitors as anticancer agents.


2022 ◽  
Vol 79 (1) ◽  
Author(s):  
Tamás Hegedűs ◽  
Markus Geisler ◽  
Gergely László Lukács ◽  
Bianka Farkas

AbstractTransmembrane (TM) proteins are major drug targets, but their structure determination, a prerequisite for rational drug design, remains challenging. Recently, the DeepMind’s AlphaFold2 machine learning method greatly expanded the structural coverage of sequences with high accuracy. Since the employed algorithm did not take specific properties of TM proteins into account, the reliability of the generated TM structures should be assessed. Therefore, we quantitatively investigated the quality of structures at genome scales, at the level of ABC protein superfamily folds and for specific membrane proteins (e.g. dimer modeling and stability in molecular dynamics simulations). We tested template-free structure prediction with a challenging TM CASP14 target and several TM protein structures published after AlphaFold2 training. Our results suggest that AlphaFold2 performs well in the case of TM proteins and its neural network is not overfitted. We conclude that cautious applications of AlphaFold2 structural models will advance TM protein-associated studies at an unexpected level.


2021 ◽  
Vol 11 (2) ◽  
pp. 57-64
Author(s):  
S. Binay Yaz ◽  
S. Başdemir

To determine the attitudes and behaviors of parents who have children between 0-12 years of age towards rational drug use during the pandemic period.


Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 176
Author(s):  
Alicia Ioppolo ◽  
Melissa Eccles ◽  
David Groth ◽  
Giuseppe Verdile ◽  
Mark Agostino

γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Solomon Ahmed Mohammed ◽  
Abebe Getie Faris

Introduction. Rational medicine use is an appropriate prescribing, dispensing, and patient use of medicines for the diagnosis, prevention, and treatment of diseases. It is affected by several factors. Irrational use of medicine is a widespread problem at all levels of care. This review is aimed at assessing the medicine use pattern in health facilities of Ethiopia using the medicine use pattern developed by WHO/INRUD. Methods. Relevant literature was searched from Google Scholar, PubMed, Hinari, Web of Science, and Scopus using inclusion and exclusion criteria. A systematic review was used to summarize the medicine use pattern in health facilities of Ethiopia, and that WHO core drug use indicators were employed. Result. From 188 searched studies, 30 literatures were reviewed. The average number of drugs per encounter was 2.11. The percentage of encounters with antibiotics and injection was 57.16% and 22.39%, respectively. The percentage of drugs prescribed by generic name and from an essential drug list was 91.56% and 90.19%, respectively. On average, patients spent 5.14 minutes for consultation and 106.52 seconds for dispensing. From prescribed drugs, 67.79% were dispensed, while only 32.25% were labeled adequately. The availability of key essential medicines was 64.87%. The index of rational drug use value was 7.26. Moreover, the index of rational drug prescribing, index of rational patient-care drug use, and index of rational facility-specific drug use were 3.74, 2.51, and 1.01, respectively. Conclusion. Ethiopian health facilities were faced with antibiotic overprescribing, short consultation, and dispensing times, poor labeling of medicines, poor availability of key drugs, and nonadherence to the essential drug list. Routine, multidisciplinary awareness creation, and regulation should be implemented to promote rational medicine use at a national level.


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