Search

In Vietnam, the stems and roots of the Rutaceous plant Paramignya trimera (Oliv.) Burkill (known locally as "Xáo tam phân") are widely used to treat liver diseases such as viral hepatitis and acute and chronic cirrhosis. In an effort to search for Vietnamese natural compounds capable of inhibiting coronavirus based on molecular docking screening, two new dimeric coumarin glycosides, namely cis-paratrimerin B (1) and cis-paratrimerin A (2), and two previously identified coumarins, the trans-isomers paratrimerin B (3) and paratrimerin A (4), were isolated from the roots of P. trimera and tested for their anti-angiotensin-converting enzyme 2 (ACE-2) inhibitory properties in vitro. It was discovered that ACE-2 enzyme was inhibited by cis-paratrimerin B (1), cis-paratrimerin A (2), and trans-paratrimerin B (3), with IC 50 values of 28.9, 68, and 77 µM, respectively. Docking simulations revealed that four biscoumarin glycosides had good binding energies (∆G values ranging from -10.6 to -14.7 kcal/mol) and mostly bound to the S1' subsite of the ACE-2 protein. The key interactions of these natural ligands include metal chelation with zinc ions and multiple H-bonds with Ser128, Glu145, His345, Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots occur naturally in both cis- and trans-diastereomeric forms. The biscoumarin glycosides Lys363, Thr371, Glu406, and Tyr803. Our findings demonstrated that biscoumarin glycosides from P. trimera roots hold potential for further studies as natural ACE-2 inhibitors for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

From the root bark of Pinus krempfii Lecomte, four flavonoids were isolated and evaluated for their inhibitory activities against AChE and BChE enzymes in vitro and in silico . Tectochrysin ( 1 ) was found to inhibit AChE with an IC 50 value of 33.69 ± 2.80 μM. The docking study results also showed agreement with the in vitro test results. All four compounds also showed the best binding affinity for the AChE enzyme, characterised by binding energy (ΔG) values as low as -8.1 to -9.3 kcal/mol, in which, the compound tectochrysin had the best binding affinity for the AChE protein with a ΔG value of -9.329 kcal/mol. Tectochrysin ( 1 ) was also bound to the amino acid Phe295 of AChE with a bond length of 2.8 Å, similar to the control dihydrotanshinone-I. Galangin ( 2 ) also showed its in vitro inhibitory activity against BChE with an IC 50 value of 82.21 ± 2.70 μM. In silico , it also had the best binding energy value of -9.072 kcal/mol with BChE and formed hydrogen bonds with the His438 (2.85 Å) residues of BChE like the positive control (tacrine). The steered molecular dynamics (SMD) simulation results of these two complexes revealed a mechanistic insight that the protein-ligand complexes showed stable trajectories throughout the 20 and 150 ns simulations. Moreover, the drug likeliness suggested that both flavonoids ( 1 and 2 ) were expected to be drug-like and have an LD 50 toxicity level of 5. This study has contributed new results for drug discovery and the development of substances with neuroprotective effects, especially for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

Background and Purpose: The carbazole alkaloid murrayafoline A (MuA) enhances contractility and the Ca(2+) currents carried by the Cav 1.2 channels [ICa1.2 ] of rat cardiomyocytes. As only few drugs stimulate ICa1.2 , this study was designed to analyse the effects of MuA on vascular Cav 1.2 channels., Experimental Approach: Vascular activity was assessed on rat aorta rings mounted in organ baths. Cav 1.2 Ba(2+) current [IBa1.2 ] was recorded in single rat aorta and tail artery myocytes by the patch-clamp technique. Docking at a 3D model of the rat, α1c central pore subunit of the Cav 1.2 channel was simulated in silico., Key Results: In rat aorta rings MuA, at concentrations ≤14.2 μM, increased 30 mM K(+) -induced tone and shifted the concentration-response curve to K(+) to the left. Conversely, at concentrations >14.2 μM, it relaxed high K(+) depolarized rings and antagonized Bay K 8644-induced contraction. In single myocytes, MuA stimulated IBa1.2 in a concentration-dependent, bell-shaped manner; stimulation was stable, incompletely reversible upon drug washout and accompanied by a leftward shift of the voltage-dependent activation curve. MuA docked at the α1C subunit central pore differently from nifedipine and Bay K 8644, although apparently interacting with the same amino acids of the pocket. Neither Bay K 8644-induced stimulation nor nifedipine-induced block of IBa1.2 was modified by MuA., Conclusions and Implications: Murrayafoline A is a naturally occurring vasoactive agent able to modulate Cav 1.2 channels and dock at the α1C subunit central pore in a manner that differed from that of dihydropyridines., (© 2015 The British Pharmacological Society.)

The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza(®), widely known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2- furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl (5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5- to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that compounds 5a and 5d displayed high affinities towards HDAC2 and 8.