Identification of potent inhibitors for Leishmania donovani homoserine kinase: an integrated in silico and kinetic study DOI
Mohini Soni, Gaurava Srivastava, Ramalingam Karthik Raja

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2023, Volume and Issue: unknown, P. 1 - 16

Published: Nov. 14, 2023

Leishmaniasis is caused by ∼20 species of Leishmania that affects millions in endemic areas. Available therapies are not sufficient to effectively control the disease, cause severe side effects and eventually lead drug resistance, making discovery novel therapeutic molecules an immediate need. Molecular target-based discovery, where target a defined molecular gene, protein or mechanism, rationale driven approach for therapeutics. Humans obtain essential amino acid such as threonine from dietary sources, while synthesize it de-novo. Enzymes biosynthesis pathway, including rate limiting Homoserine kinase (HSK) which converts L-homoserine into ortho-phospho homoserine thus attractive targets therapy. The absence HSK humans its presence donovani enhances opportunity exploit anti-leishmanials development. In this study, we utilize structure-based high throughput (SBDD), followed biochemical validation identified two potential inhibitors (RH00038 S02587) Maybridge chemical library L. HSK. These induced mortality both amastigote promastigote stages, with one them being specific parasite twice effective standard molecule.

Language: Английский

Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery DOI Creative Commons
Liang Leng, Zhichao Xu,

Bixia Hong

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 20, 2024

Abstract Cepharanthine is a secondary metabolite isolated from Stephania . It has been reported that it anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three genomes ( S. japonica , yunnanensis and cepharantha ), propose the cepharanthine biosynthetic pathway, assess antiviral potential of compounds involved in pathway. Among genomes, near telomere-to-telomere assembly with one remaining gap, have chromosome-level assemblies. Following by gene mining metabolomics analysis, identify seven analogs broad-spectrum anti-coronavirus activities, SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine diarrhoea coronavirus (SADS-CoV), porcine epidemic diarrhea virus (PEDV). We also show two other genera, Nelumbo Thalictrum can produce analogs, thus for compound discovery. Results generated this study could accelerate drug

Language: Английский

Citations

35
Identifying Inhibitor-SARS-CoV2-3CLpro Binding Mechanism Through Molecular Docking, GaMD Simulations, Correlation Network Analysis and MM-GBSA Calculations DOI Creative Commons
Jianzhong Chen, Jian Wang, Wanchun Yang

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(4), P. 805 - 805

Published: Feb. 10, 2025

The main protease of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known as 3CLpro, is crucial in virus's life cycle and plays a pivotal role COVID-19. Understanding how small molecules inhibit 3CLpro's activity vital for developing anti-COVID-19 therapeutics. To this end, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to enhance sampling 3CLpro conformations conducted correlation network analysis (CNA) explore interactions between different structural domains. Our findings indicate that CNA-identified node domain II acts conduit, transferring conformational changes from catalytic regions domains I II, triggered by binding inhibitors (7YY, 7XB, Y6G), III, thereby modulating activity. Normal mode (NMA) principal component (PCA) revealed inhibitor affects flexibility collective movements sites influencing function. free energies, predicted both MM-GBSA QM/MM-GBSA methods, showed high with experimental data, validating reliability our analyses. Furthermore, residues L27, H41, C44, S46, M49, N142, G143, S144, C145, H163, H164, M165, E166, identified through residue-based energy decomposition, present promising targets design drugs could facilitate development clinically effective inhibitors.

Language: Английский

Citations

4
New trends in the practical use of isoquinoline alkaloids as potential drugs applicated in infectious and non-infectious diseases DOI Open Access
Tomasz Tuzimski, Anna Petruczynik

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 168, P. 115704 - 115704

Published: Oct. 19, 2023

In the last years, traditional natural products have been center of attention for scientific community and exploration their therapeutic abilities is proceeding permanently. Isoquinoline alkaloids always attracted interest due to either positive or negative effects on human organism. The present review describes research isoquinoline isolated from different plant species. Alkaloids are one most important classes derived compounds among these possess varied biological activities such as anticancer, antineurodegenerative diseases, antidiabetic, antiinflammatory, antimicrobial, many others. use plants against disorders entrenched in medicine around globe. Recent progress modern therapeutics has stimulated worldwide various ailments diseases. provides a collection information capabilities some alkaloids, its potential treatment diseases designed be guide future biologically active species containing them. authors aware that they were not able cover whole area topic related activity alkaloids. This intended suggest directions further can also help other researchers studies.

Language: Английский

Citations

16
Aurones: A Promising Scaffold to Inhibit SARS-CoV-2 Replication DOI
Guilherme S. Caleffi, Alice dos Santos Rosa, Luana G. de Souza

et al.

Journal of Natural Products, Journal Year: 2023, Volume and Issue: 86(6), P. 1536 - 1549

Published: May 31, 2023

Aurones are a small subgroup of flavonoids in which the basic C6–C3–C6 skeleton is arranged as (Z)-2-benzylidenebenzofuran-3(2H)-one. These compounds structural isomers flavones and flavonols, natural products reported potent inhibitors SARS-CoV-2 replication. Herein, we report design, synthesis, anti-SARS-CoV-2 activity series 25 aurones bearing different oxygenated groups (OH, OCH3, OCH2OCH3, OCH2O, OCF2H, OCH2C6H4R) at A- and/or B-rings using cell-based screening assays. We observed that 12 exhibit EC50 < 3 μM (8e, 8h, 8j, 8k, 8l, 8m, 8p, 8q, 8r, 8w, 8x, 8y), five presented 1 (8h, 8w) without evident cytotoxic effect Calu-3 cells. The substitution B-ring with OCF2H seems beneficial for antiviral activity, while corresponding phenolic derivatives showed significant decrease activity. most compound series, aurone 8q (EC50 = 0.4 μM, SI 2441.3), 2 to times more effective than polyphenolic myricetin (2) baicalein (1), respectively. Investigation active 3CLpro based on molecular dynamic calculations suggested these should detach from site 3CLpro, and, probably, they could bind another protein target (either receptor or enzyme).

Language: Английский

Citations

14
Inhibitory Activity of Flavonoid Scaffolds on SARS-CoV-2 3CLpro: Insights from the Computational and Experimental Investigations DOI
Nopawit Khamto, Kraikrit Utama, Panida Boontawee

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(3), P. 874 - 891

Published: Jan. 26, 2024

The emergence of the COVID-19 situation has become a global issue due to lack effective antiviral drugs for treatment. Flavonoids are class plant secondary metabolites that have activity against SARS-CoV-2 through inhibition main protease (3CLpro). In this study, 22 flavonoids obtained from natural sources and semisynthetic approaches were investigated their inhibitory 3CLpro, along with cytotoxicity on Vero cells. protein–ligand interactions examined using molecular dynamics simulation. Moreover, QSAR analysis was conducted clarify structural effects bioactivity. Accordingly, in vitro investigation demonstrated four flavonoids, namely, tectochrysin (7), 6″,6″-dimethylchromeno-[2″,3″:7,8]-flavone (9), panduratin A (19), genistein (20), showed higher compared standard flavonoid baicalein. Finally, our finding suggests an isoflavone discovered Millettia brandisiana, potential further development as 3CLpro inhibitor.

Language: Английский

Citations

5
Virucidal Activity of Tiliacorinine, Dioscorine, Racemosol, and Terrein against Influenza A Virus (H1N1), Coronavirus 229E, SARS-CoV-2, and Enterovirus 71 DOI Creative Commons
Akanitt Jittmittraphap, Pornsawan Leaungwutiwong,

Piyawan Meechokedee

et al.

Journal of Infection and Public Health, Journal Year: 2025, Volume and Issue: 18(4), P. 102699 - 102699

Published: Feb. 12, 2025

Emerging infectious diseases such as COVID-19 and Disease X, which was detected in the Democratic Republic of Congo early December 2024, underscore importance developing new virucidal, antiviral, antimicrobial compounds. The virucidal activity natural products, including tiliacorinine (1), dioscorine (2), racemosol (3), terrein (4), against influenza A virus (H1N1), human coronavirus 229E (HCoV-229E), severe acute respiratory syndrome 2 (SARS-CoV-2), enterovirus 71 (EV71) were evaluated using American Society for Testing Materials E1053-20 method. Racemosol (3) from Bauhinia malabarica had most potent H1N1, HCoV-229E, SARS-CoV-2 viruses, followed by a metabolite fungus Aspergillus terreus. exhibited with log reduction 4 (99.99 % viral reduction) at concentration 0.1250 mg/mL. alkaloids (1) Tiliacora triandra (2) Dioscorea hispida weaker than (4). Compounds 1, 2, showed weak EV71 virus, while displayed moderate 3.813 This work underscores products sources agents, may be useful future threats emerging re-emerging diseases.

Language: Английский

Citations

0
Effects of organic salts of virucidal and antiviral compounds from Nelumbo nucifera and Kaempferia parviflora against SARS-CoV-2 DOI Creative Commons
Dandan Yang, Nopporn Chutiwitoonchai, Feng Wang

et al.

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 21, 2025

The present work investigates virucidal and antiviral compounds in the extracts of seed embryos a lotus, Nelumbo nucifera, Thai ginseng, Kaempferia parviflora. Separation led to identification against SARS-CoV-2. Neferine (1) nuciferine (3) from N. as well their respective HCl salts (2 4), exhibited activities Virucidal activity neferine salt (2) (EC50 4.78 µM) was 7.5 times better than its free-base, 36.01 µM), also improved selectivity index (SI), showing less cytotoxicity 1. This demonstrates that organic have an impact on biological activities. A crude extract K. parviflora rhizomes displayed 42.11 µg/mL) 39.28 µg/mL). Isolation nine flavonoids (5–13). Among these flavonoids, only 5,7,4'-trimethoxyflavone (8) found show 437.90 50.97 However, (5–13) did not inhibit SARS-CoV-2 3CLpro enzyme at concentrations 10 µM 100 µM. In conclusion, our data underscores therapeutic potential nucifera derived bioactive

Language: Английский

Citations

0
Stand Up to Stand Out: Natural Dietary Polyphenols Curcumin, Resveratrol, and Gossypol as Potential Therapeutic Candidates against Severe Acute Respiratory Syndrome Coronavirus 2 Infection DOI Open Access
Zhonglei Wang, Xian-qing Song,

Wenjing Xu

et al.

Nutrients, Journal Year: 2023, Volume and Issue: 15(18), P. 3885 - 3885

Published: Sept. 6, 2023

The COVID-19 pandemic has stimulated collaborative drug discovery efforts in academia and the industry with aim of developing therapies vaccines that target SARS-CoV-2. Several novel have been approved deployed last three years. However, their clinical application revealed limitations due to rapid emergence viral variants. Therefore, development next-generation SARS-CoV-2 therapeutic agents a high potency safety profile remains priority for global health. Increasing awareness “back nature” approach improving human health prompted renewed interest natural products, especially dietary polyphenols, as an additional strategy treat patients, owing its good profile, exceptional nutritional value, health-promoting benefits (including potential antiviral properties), affordability, availability. Herein, we describe biological properties pleiotropic molecular mechanisms polyphenols curcumin, resveratrol, gossypol inhibitors against variants observed vitro vivo studies. Based on advantages disadvantages obtain maximal benefits, several strategies such nanotechnology (e.g., curcumin-incorporated nanofibrous membranes antibacterial-antiviral ability), lead optimization methylated analog curcumin), combination specific plant extracts micronutrients), broad-spectrum activities broadly inhibits coronaviruses) also emphasized positive factors facilitation anti-SARS-CoV-2 support effective long-term management control.

Language: Английский

Citations

9
Potential of umami molecules against SARS-CoV-2 (Omicron) S-RBD/hACE2 interaction: an in-silico study DOI
Zhiyong Cui, Shengnan Wang,

Yeling Xu

et al.

Journal of Future Foods, Journal Year: 2024, Volume and Issue: 5(3), P. 283 - 294

Published: Sept. 24, 2024

Language: Английский

Citations

3
A novel in-silico strategy for the combined inhibition of intestinal bacterial resistance and the transfer of resistant genes using new fluoroquinolones, antibiotic adjuvants, and phytochemicals DOI

Qikun Pu,

Zhonghe Wang, Tong Li

et al.

Food Bioscience, Journal Year: 2024, Volume and Issue: 62, P. 105036 - 105036

Published: Sept. 6, 2024

Language: Английский

Citations

2