Leal, Emilse S. published the artcileDe novo design approaches targeting an envelope protein pocket to identify small molecules against dengue virus, Related Products of alcohols-buliding-blocks, the publication is European Journal of Medicinal Chemistry (2019), 111628, database is CAplus and MEDLINE.
Dengue fever is a mosquito-borne viral disease that has become a major public health concern worldwide. This disease presents with a wide range of clin. manifestations, from a mild cold-like illness to the more serious hemorrhagic dengue fever and dengue shock syndrome. Currently, neither an approved drug nor an effective vaccine for the treatment are available to fight the disease. The envelope protein (E) is a major component of the virion surface. This protein plays a key role during the viral entry process, constituting an attractive target for the development of antiviral drugs. The crystal structure of the E protein reveals the existence of a hydrophobic pocket occupied by the detergent n-octyl-β-d-glucoside (β-OG). This pocket lies at the hinge region between domains I and II and is important for the low pH-triggered conformational rearrangement required for the fusion of the virion with the host’s cell. Aiming at the design of novel mols. which bind to E and act as virus entry inhibitors, we undertook a de novo design approach by “growing” mols. inside the hydrophobic site (β-OG). From more than 240000 small-mols. generated, the 2,4 pyrimidine scaffold was selected as the best candidate, from which one synthesized compound displayed micromolar activity. Mol. dynamics-based optimization was performed on this hit, and thirty derivatives were designed in silico, synthesized and evaluated on their capacity to inhibit dengue virus entry into the host cell. Four compounds were found to be potent antiviral compounds in the low-micromolar range. The assessment of drug-like physicochem. and in vitro pharmacokinetic properties revealed that compounds 3e and 3h presented acceptable solubility values and were stable in mouse plasma, simulated gastric fluid, simulated intestinal fluid, and phosphate buffered saline solution pyrimidine.
European Journal of Medicinal Chemistry published new progress about 622-40-2. 622-40-2 belongs to alcohols-buliding-blocks, auxiliary class Morpholine,Alcohol, name is 2-Morpholinoethanol, and the molecular formula is C6H13NO2, Related Products of alcohols-buliding-blocks.
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