A theoretical screening of phytochemical constituents from Millettia brandisiana as inhibitors against acetylcholinesterase.

Alzheimer's disease is one of the causes associated with the early stages of dementia. Nowadays, the main treatment available is to inhibit the actions of the acetylcholinesterase (AChE) enzyme, which has been identified as responsible for the disease. In this study, computational methods were used to examine the structure and therapeutic ability of chemical compounds extracted from Millettia brandisiana natural products against AChE. This plant is commonly known as a traditional medicine in Vietnam and Thailand for the treatment of several diseases. Furthermore, machine learning helped us narrow down the choice of 85 substances for further studies by molecular docking and molecular dynamics simulations to gain deeper insights into the interactions between inhibitors and disease proteins. Of the five top-choice substances, γ-dimethylallyloxy-5,7,2,5-tetramethoxyisoflavone emerges as a promising substance due to its large free binding energy to AChE and the high thermodynamic stability of the resulting complex.

Identification of new anti-mycobacterial agents based on quinoline-isatin hybrids targeting enoyl acyl carrier protein reductase (InhA).

Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.

In Vitro and in Silico Study of New Biscoumarin Glycosides from Paramignya trimera against Angiotensin-Converting Enzyme 2 (ACE-2) for Preventing SARS-CoV-2 Infection.

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 IC50 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.

Chemical Compositions and Antimicrobial and Mosquito Larvicidal Activities of the Leaf Essential Oils of Goniothalamus yunnanensis W.T.Wang and G. touranensis Ast: Experimental and In Silico Approaches.

The current research describes a phytochemical analysis and antimicrobial activity of essential oils extracted from the leaves of two Vietnamese Annonaceae species Goniothalamus yunnanensis W.T.Wang and G. touranensis Ast. By the GC-FID/MS (gas chromatography-flame ionization detection/mass spectrometry) analyses, sesquiterpene hydrocarbons accounted for the highest percentage of 68.22% in G. yunnanensis leaf essential oil with bicyclogermacrene (31.03%) and (E)-caryophyllene (21.12%) being the main compounds. G. touranensis leaf essential oil was dominated by monoterpene hydrocarbons (57.08%) with p-cymene (19.95%) and α-pinene (16.82%) being the major compounds. Two oil samples showed strong antibacterial effects on the Gram-positive bacteria Enterococcus faecalis ATCC51299, Staphylococcus aureus ATCC29213, and Bacillus cereus ATCC11778 with the MIC values of 16-64 µg/mL. They also inhibited the growth of the yeast Candida albicans ATCC 60193 with the same MIC value of 128 µg/mL. Both two oil samples showed strong mosquito larvicidal activity against four-instar larvae of Aedes aegypti and Ae. albopictus with the 24-h LC50 values of 16.75-27.60 µg/mL and 24-h LC90 values of 24.31-46.18 µg/mL. Docking results indicated that bicyclogermacrene and p-cymene exhibited the highest ΔG (binding affinity) values of -8.208 and -6.799 kcal/mol with the olfactory binding proteins (OBPs) of Ae. aegypti and Ae. albopictus, respectively.

Chemical Composition, Mosquito Larvicidal and Antimicrobial Activities, and Molecular Docking Study of Essential Oils of Cinnamomum melastomaceum, Neolitsea buisanensis and Uvaria microcarpa from Vietnam.

The leaf oil compositions of two Lauraceae and one Annonaceae plants cultivated in Vietnam were analysed by GC/MS (gas chromatography-mass spectrometry) analysis. The leaf oil of the first Lauraceae plant Cinnamomum melastomaceum contained 34 identified compounds, in which benzyl benzoate (38.5 %), linalool (19.9 %), (E)-caryophyllene (10.5 %), and α-terpineol (6.9 %) were the major compounds. The leaves of the second Lauraceae plant Neolitsea buisanensis gave an oil with the main compounds (E)-ß-ocimene (24.0 %), benzyl benzoate (15.8 %), bicyclogermacrene (14.9 %), and (E)-caryophyllene (6.3 %). The leaf oil of the Annonaceae plant Uvaria microcarpa consisted of the principal compounds (E)-caryophyllene (18.0 %), bicyclogermacrene (8.1 %), and δ-elemene (6.1 %). Two Lauraceae oil samples exhibited strong mosquito larvicidal activity against Aedes aegypti, Ae. albopictus, and Culex quinquefasciatus with LC50 and LD90 values of less than 50 µg/mL. The Annonaceae oil sample showed strong antimicrobial activity against the fungus Aspergillus niger ATCC 1015 with the MIC (minimum inhibitory concentration) value of 32 µg/mL. In the docking approach, the major compounds (E)-caryophyllene, bicyclogermacrene, and benzyl benzoate interacted with the mosquito odorant-binding protein 3OGN, whereas (E)-caryophyllene, bicyclogermacrene, and δ-elemene also potentially interacted with the 4ZA5 protein of fungus A. niger.

Anti-Alzheimer's Activity of Polyphenolic Stilbene-Rich Acetone Fraction of the Oil-Removed Seeds of Passiflora edulis: in Vivo and in Silico Studies.

The stilbene-rich acetone fraction in high yield (6.6 %, PEAS) of Passiflora edulis Sims was prepared and evaluated for neuroprotective activity in murine Alzheimer's disease model induced by aluminum chloride and D-galactose. The phytochemical and HPLC-DAD-MS analysis of the polyphenolic stilbene-rich acetone fraction showed that it contained different stilbenes including trans-piceatannol, scirpusins A-B and cassigarol E. The total phenolic content (TPC) of PEAS was 413.87±1.71 mg GAE eqv/g. The neuroprotective activity of PEAS is typically presented in the Morris water maze-reference Spatial Memory test, where the Alzheimer's mice treated at 100 mg/kg (Alz-ED1) and 200 mg/kg (Alz-ED2) spent less than 47 % and 66 % of the time, respectively, than the Alzheimer's model mice (Alz). Two simple stilbenes, trans-piceatannol and trans-resveratrol, showed selectively inhibitory activity in silico against acetylcholinesterase (AChE). Two stilbene dimers, cassigarol E and scirpusin A, exhibited low nanomolar inhibitory potential against AChE and butyrylcholinesterase (BChE), significantly lower than those of the positive control, donepezil and tacrine. These findings suggest that the stilbenes from P. edulis seeds, particularly the stilbene dimers, warrant further investigation as potential neuroprotective candidates in the prevention of cognitive deficits associated with Alzheimer's disease.

Natural Phosphodiesterase-4 Inhibitors with Potential Anti-Inflammatory Activities from Millettia dielsiana.

The results of in silico screening of the 50 isolated compounds from Millettia dielsiana against the target proteins PDE4 (PDE4A, PDE4B, and PDE4D) showed binding affinity ranges from -5.81 to -11.56, -5.27 to -13.01, and -5.80 to -12.12 kcal mol-1, respectively, with median values of -8.83, -8.84, and -8.645 kcal mol-1, respectively. Among these compounds, Millesianin F was identified as the most promising PDE4A inhibitor due to its strongest binding affinity with the target protein PDE4A. (-11.56 kcal mol-1). This was followed by the compound 5,7,4'-trihydroxyisoflavone 7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside (D50) with the binding affinity value of -11.35 kcal mol-1. For the target protein PDE4B, compound D50 exhibited the strongest binding affinity value of -13.01 kcal mol-1, while showing poorer inhibition ability for PDE4D. The 100 ns MD simulation examination (radius of gyration, Solvent Accessible Surface Area (SASA), Root-Mean-Square Deviation (RMSD), Root-Mean-Square Fluctuation (RMSF), and hydrogen bonding) was carried out to examine the overall stability and binding efficiency of the protein-ligand complex between compounds (Millesianin F, Millesianin G, Claclrastin-7-O-ß-d-glucopyranoside, 7-hydroxy-4',6 dimethoxyisoflavone-7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside, 7-hydroxy-4',8-dimethoxyisoflavone 7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside, Odoratin-7-O-ß-d-glucopyranoside, and 5,7,4'-trihydroxyisoflavone 7-O-ß-d-apiofuranosyl-(1→6)-ß-d-glucopyranoside) and PDE4 (A, B) subtype proteins. Compound D50 has shown strong anti-inflammatory activity, as evidenced by experimental results. It effectively inhibits PDE4B and PDE4D, with IC50 values of 6.56 ± 0.7 µM and 11.74 ± 1.3 µM, respectively. Additionally, it reduces NO production, with an IC50 value of 5.40 ± 0.9 µM. Based on these findings, it is promising and considered a potential novel anti-inflammatory drug for future development.

Acetylcholinesterase inhibitory activities of some flavonoids from the root bark of Pinus krempfii Lecomte: in vitro and in silico study.

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 IC50 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 IC50 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 LD50 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.

Computational estimation of potential inhibitors from known drugs against the main protease of SARS-CoV-2.

The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide recently, leading to global social and economic disruption. Although the emergently approved vaccine programs against SARS-CoV-2 have been rolled out globally, the number of COVID-19 daily cases and deaths has remained significantly high. Here, we attempt to computationally screen for possible medications for COVID-19 via rapidly estimating the highly potential inhibitors from an FDA-approved drug database against the main protease (Mpro) of SARS-CoV-2. The approach combined molecular docking and fast pulling of ligand (FPL) simulations that were demonstrated to be accurate and suitable for quick prediction of SARS-CoV-2 Mpro inhibitors. The results suggested that twenty-seven compounds were capable of strongly associating with SARS-CoV-2 Mpro. Among them, the seven top leads are daclatasvir, teniposide, etoposide, levoleucovorin, naldemedine, cabozantinib, and irinotecan. The potential application of these drugs in COVID-19 therapy has thus been discussed.