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Fulltext Design of new competitive dengue NS2B/NS3 protease inhibitors-a computational approach

Frimayanti N, Chee CF, Zain SM, Rahman NA

Int J Mol Sci, 2011;12(2):1089-100.
PMID: 21541045 DOI: 10.3390/ijms12021089

Dengue is a serious disease which has become a global health burden in the last decade. Currently, there are no approved vaccines or antiviral therapies to combat the disease. The increasing spread and severity of the dengue virus infection emphasizes the importance of drug discovery strategies that could efficiently and cost-effectively identify antiviral drug leads for development into potent drugs. To this effect, several computational approaches were applied in this work. Initially molecular docking studies of reference ligands to the DEN2 NS2B/NS3 serine protease were carried out. These reference ligands consist of reported competitive inhibitors extracted from Boesenbergia rotunda (i.e., 4-hydroxypanduratin A and panduratin A) and three other synthesized panduratin A derivative compounds (i.e., 246DA, 2446DA and 20H46DA). The design of new lead inhibitors was carried out in two stages. In the first stage, the enzyme complexed to the reference ligands was minimized and their complexation energies (i.e., sum of interaction energy and binding energy) were computed. New compounds as potential dengue inhibitors were then designed by putting various substituents successively on the benzyl ring A of the reference molecule. These substituted benzyl compounds were then computed for their enzyme-ligand complexation energies. New enzyme-ligand complexes, exhibiting the lowest complexation energies and closest to the computed energy for the reference compounds, were then chosen for the next stage manipulation and design, which involved substituting positions 4 and 5 of the benzyl ring A (positions 3 and 4 for 2446DA) with various substituents.

Matched MeSH terms: Serine Proteinase Inhibitors/pharmacology
Synthesis, spectral analysis and biological evaluation of Nalkyl/aralkyl/aryl-4-chlorobenzenesulfonamide derivatives

Rehman A, Abbasi MA, Siddiqui SZ, Mohyuddin A, Nadeem S, Shah SA

Pak J Pharm Sci, 2016 Sep;29(5):1489-1496.
PMID: 27731801

New potent organic compounds were synthesized with an aim of good biological activities such as antibacterial and anti-enzymatic. Three series of sulfonamide derivatives were synthesized by treating N-alkyl/aryl substituted amines (2a-f) with 4-chlorobenzensulfonyl chloride (1) to yield N-alkyl/aryl-4-chlorobenzenesulfonamide(3af) that was then derivatized by gearing up with ethyl iodide (4), benzyl chloride (5) and 4-chlorobenzyl chloride (6) using sodium hydride as base to initialize the reaction in a polar aprotic solvent (DMF) to synthesize the derivatives, 7a-f, 8af and 9a-f respectively. Structure elucidation was brought about by IR, 1H-NMR and EIMS spectra for all the synthesized molecules which were evaluated for their antibacterial activities and inhibitory potentials for certain enzymes.

Matched MeSH terms: Serine Proteinase Inhibitors/pharmacology
Recent update on anti-dengue drug discovery

Dighe SN, Ekwudu O, Dua K, Chellappan DK, Katavic PL, Collet TA

Eur J Med Chem, 2019 Aug 15;176:431-455.
PMID: 31128447 DOI: 10.1016/j.ejmech.2019.05.010

Dengue is the most important arthropod-borne viral disease of humans, with more than half of the global population living in at-risk areas. Despite the negative impact on public health, there are no antiviral therapies available, and the only licensed vaccine, Dengvaxia®, has been contraindicated in children below nine years of age. In an effort to combat dengue, several small molecules have entered into human clinical trials. Here, we review anti-DENV molecules and their drug targets that have been published within the past five years (2014-2018). Further, we discuss their probable mechanisms of action and describe a role for classes of clinically approved drugs and also an unclassified class of anti-DENV agents. This review aims to enhance our understanding of novel agents and their cognate targets in furthering innovations in the use of small molecules for dengue drug therapies.

Matched MeSH terms: Serine Proteinase Inhibitors/pharmacology*
Comparative aspects of the care of familial hypercholesterolemia in the "Ten Countries Study"

Pang J, Chan DC, Hu M, Muir LA, Kwok S, Charng MJ, et al.

J Clin Lipidol, 2019 01 25;13(2):287-300.
PMID: 30797720 DOI: 10.1016/j.jacl.2019.01.009

BACKGROUND: There is a lack of information on the health care of familial hypercholesterolemia (FH).
OBJECTIVE: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere.
METHODS: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark.
RESULTS: The estimated percentage of patients diagnosed with the condition was low (overall <3%) in all countries, compared with ∼15% in the UK. Underdetection of FH was associated with government expenditure on health care (ϰ = 0.667, P

Matched MeSH terms: Serine Proteinase Inhibitors/pharmacology