945895-76-1Relevant academic research and scientific papers
De novo design approaches targeting an envelope protein pocket to identify small molecules against dengue virus
Acosta Dávila, John Alejandro,Adler, Natalia S.,Aucar, Maria G.,Battini, Leandro,Bollini, Mariela,Cavasotto, Claudio N.,Cordo, Sandra M.,Fernández, Gabriela A.,Gamarnik, Andrea V.,García, Cybele C.,Gebhard, Leopoldo G.,Hernández de los Ríos, Alejandro,Leal, Emilse S.,Monge, María Eugenia,Morell, María L.,Videla, Mariela
, (2019)
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 clinical 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 molecules which bind to E and act as virus entry inhibitors, we undertook a de novo design approach by “growing” molecules inside the hydrophobic site (β-OG). From more than 240000 small-molecules generated, the 2,4 pyrimidine scaffold was selected as the best candidate, from which one synthesized compound displayed micromolar activity. Molecular 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 physicochemical 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.
Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: Development of chemical probe ML315
Coombs, Thomas C.,Tanega, Cordelle,Shen, Min,Wang, Jenna L.,Auld, Douglas S.,Gerritz, Samuel W.,Schoenen, Frank J.,Thomas, Craig J.,Aubé, Jeffrey
supporting information, p. 3654 - 3661 (2013/07/05)
Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk
Development and evaluation of multifunctional agents for potential treatment of Alzheimer's disease: Application to a pyrimidine-2,4-diamine template
Mohamed, Tarek,Yeung, Jacky C.K.,Vasefi, Maryam S.,Beazely, Michael A.,Rao, Praveen P.N.
supporting information; experimental part, p. 4707 - 4712 (2012/08/13)
We investigated a group of 2-benzylpiperidin-N-benzylpyrimidin-4-amines with various electron-withdrawing or electron-donating groups (EWGs or EDGs, respectively) as multi-targeted Alzheimer's disease (AD) therapeutics. The synthesized derivatives were sc
