From Flora to Pharmaceuticals: 100 new additions to angiosperms of Gafargaon subdistrict in Bangladesh and unraveling antidiabetic drug candidates targeting DPP4 through in silico approach.

Addition to the angiosperm flora provides essential insights into the biodiversity of a region, contributing to ecological understanding and conservation planning. Gafargaon subdistrict under Mymensingh district in Bangladesh represents a diverse population of angiosperms with a multifaceted ecosystem that demands re-evaluation of the existing angiosperm diversity of Gafargaon to update the status of angiosperm taxa and facilitate their conservation efforts. With this endeavor, a total of 100 angiosperm taxa belonging to 90 genera and 46 families were uncovered as additional occurrence in Gafargaon. The species in the area showcased a variety of life forms, including 63 herbs, 14 shrubs, 14 trees, and 9 climbers. Among the recorded taxa, Chamaecostus cuspidatus (Nees & Mart.) C.D. Specht & D.W. Stev. was selected for antidiabetic drug design endeavor based on citation frequency and ethnomedicinal evidence. A total of 41 phytochemicals of C. cuspidatus were screened virtually, targeting the Dipeptidyl peptidase 4 protein through structure-based drug design approach, which unveiled two lead compounds, such as Tigogenin (-9.0 kcal/mol) and Diosgenin (-8.5 kcal/mol). The lead candidates demonstrated favorable pharmacokinetic and pharmacodynamic properties with no major side effects. Molecular dynamics simulation revealed notable stability and structural compactness of the lead compounds. Principal component analysis and Gibbs free energy landscape further supported the results of molecular dynamics simulation. Molecular mechanics-based MM/GBSA approach unraveled higher free binding energies of Diosgenin (-47.36 kcal/mol) and Tigogenin (-46.70 kcal/mol) over Alogliptin (-46.32 kcal/mol). The outcome of the present investigation would enrich angiosperm flora of Gafargaon and shed light on the role of C. cuspidatus to develop novel antidiabetic therapeutics to combat diabetes.

Insight into novel inhibitors from Sterculia urens against Cholera via pharmacoinformatics and molecular dynamics simulation approaches.

The underdeveloped countries with large populations are facing a grave global threat in the form of cholera. Vibrio cholerae, the etiologic agent of Cholera has drawn attention recently due to antimicrobial resistance and resulting outbreaks that necessitates establishment of novel medications to counteract virulence and viability of the pathogen. Sterculia urens Roxb. (Malvaceae) is an ethnomedicinally important tree, which harbors a good number of bioactive phytocompounds. In the present study, 53 phytocompounds of S. urens were screened against the promising target ToxT of V. cholerae employing structure-based drug design approach that revealed three lead compounds, viz., 4,4,5,8-Tetramethylchroman-2-ol (-8.2 kcal/mol), Beta-Bisabolol (-8.2 kcal/mol) and Ledol (-8.7 kcal/mol) with satisfactory ADMET properties. Molecular dynamics simulation for 150 ns unveiled notable compactness and structural stability for the lead compounds considering RMSD, RMSF, Rg, MolSA, PSA and protein-ligand contacts parameters. Molecular mechanics-based MM/GBSA binding energy calculation revealed Beta-Bisabolol (-66.74 kcal/mol) to have better scores than 4,4,5,8-Tetramethylchroman-2-ol (-47.42 kcal/mol) and Ledol (-65.79 kcal/mol). Enzymes were mostly found as drug target class, and Nabilone was found as a structurally similar analog for 4,4,5,8-Tetramethylchroman-2-ol. These discoveries could aid in revealing new antibacterial medications targeting ToxT to combat Cholera.Communicated by Ramaswamy H. Sarma.

High-throughput virtual screening of marine algae metabolites as high-affinity inhibitors of ISKNV major capsid protein: An analysis of in-silico models and DFT calculation to find novel drug molecules for fighting infectious spleen and kidney necrosis virus (ISKNV).

Infectious Spleen and Kidney Necrosis Virus (ISKNV) is linked to severe infections that cause significant financial losses in global aquaculture. ISKNV enters the host cell through its major capsid protein (MCP), and the resulting infection can lead to mass mortality of fish. Even though several drugs and vaccines are at various stages of clinical testing, none are currently available. Thus, we sought to assess the potential of seaweed compounds to block viral entrance by inhibiting the MCP. The Seaweed Metabolite Database (1110 compounds) was assessed for potential antiviral activity against ISKNV using high throughput virtual screening. Forty compounds with docking scores of ≥8.0 kcal/mol were screened further. The inhibitory molecules BC012, BC014, BS032, and RC009 were predicted by the docking and MD techniques to bind the MCP protein significantly with binding affinities of -9.2, -9.2, -9.9, and -9.4 kcal/mol, respectively. Also, ADMET characteristics of the compounds indicated drug-likeness. According to this study, marine seaweed compounds may operate as viral entrance inhibitors. For their efficacy to be established, in-vitro and in-vivo testing is required.

Pharmacoinformatics and molecular dynamics simulation approach to identify anti-diarrheal potentials of Centella asiatica (L.) Urb. against Vibrio cholerae.

Vibrio cholerae, the etiological agent of cholera, causes dehydration and severe diarrhea with the production of cholera toxin. Due to the acquired antibiotic resistance, V. cholerae has drawn attention to the establishment of novel medications to counteract the virulence and viability of the pathogen. Centella asiatica is a medicinal herb native to Bangladesh that has a wide range of medicinal and ethnobotanical applications including anti-bacterial properties. In the present investigation, a total of 25 bioactive phytochemicals of C. asiatica have been screened virtually through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analyses, and molecular dynamics simulation. Our results revealed four lead compounds as Viridiflorol (-8.7 Kcal/mol), Luteolin (-8.1 Kcal/mol), Quercetin (-8.0 Kcal/mol) and, Geranyl acetate (-7.1 Kcal/mol) against V. cholerae Toxin co-regulated pilus virulence regulatory protein (ToxT). All the lead compounds have been found to possess favorable pharmacokinetic, pharmacodynamics, and molecular dynamics properties. Toxicity analysis revealed satisfactory results with no major side effects. Molecular dynamics simulation was performed for 100 ns that revealed noteworthy conformational stability and structural compactness for all the lead compounds, especially for Quercetin. Target class prediction unveiled enzymes in most of the cases and some experimental and investigational drugs were found as structurally similar analogs of the lead compounds. These findings could aid in the development of novel therapeutics targeting Cholera disease and we strongly recommend in vitro trials of our experimental findings.Communicated by Ramaswamy H. Sarma.

Anticancer potential of phytochemicals from Oroxylum indicum targeting Lactate Dehydrogenase A through bioinformatic approach.

In recent years, small molecule inhibition of LDHA (Lactate Dehydrogenase A) has evolved as an appealing option for anticancer therapy. LDHA catalyzes the interconversion of pyruvate and lactate in the glycolysis pathway to play a crucial role in aerobic glycolysis. Therefore, in the current investigation LDHA was targeted with bioactive phytochemicals of an ethnomedicinally important plant species Oroxylum indicum (L.) Kurz. A total of 52 phytochemicals were screened against LDHA protein through molecular docking, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) assay and molecular dynamics simulation to reveal three potential lead compounds such as Chrysin-7-O-glucuronide (-8.2 kcal/mol), Oroxindin (-8.1 kcal/mol) and Oroxin A (-8.0 kcal/mol). ADMET assay unveiled favorable pharmacokinetic, pharmacodynamic and toxicity properties for all the lead compounds. Molecular dynamics simulation exhibited significant conformational stability and compactness. MM/GBSA free binding energy calculations further corroborated the selection of top candidates where Oroxindin (-46.47 kcal/mol) was found to be better than Chrysin-7-O-glucuronide (-45.72 kcal/mol) and Oroxin A (-37.25 kcal/mol). Aldolase reductase and Xanthine dehydrogenase enzymes were found as potential drug targets and Esculin, the FDA approved drug was identified as structurally analogous to Oroxindin. These results could drive in establishing novel medications targeting LDHA to fight cancer.

Anti-angiogenic potential of bioactive phytochemicals from Helicteres isora targeting VEGFR-2 to fight cancer through molecular docking and molecular dynamics simulation.

Cancer is one of the leading causes of death due to its very high rate of morbidity and mortality, and there is a constant demand of effective drugs for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a significant role as central modulator of angiogenesis and is targeted frequently for developing anti-angiogenic agents to fight cancer. Helicteres isora L. (Malvaceae) is reported to possess diverse medicinal properties including anti-cancer potentials. In the current investigation, 38 bioactive phytochemicals of H. isora were screened virtually to evaluate their anti-angiogenic potentials targeting VEGFR-2. The study unveiled three potential candidates such as, Diosgenin (-9.8 Kcal//mol), Trifolin (-8.4 Kcal/mol) and Yohimbine (-8.1 Kcal/mol) that showed favorable pharmacokinetic, pharmacodynamic and toxicity properties with no significant side effects. Molecular dynamics simulation employing 100 ns revealed noteworthy structural stability and compactness for all the top three candidates. The MM/GBSA binding free energy estimation corroborated the docking interactions where Yohimbine (-30.47 Kcal/mol) scored better than Diosgenin (-27.54 Kcal/mol) and Trifolin (-29.58 Kcal/mol). Target class prediction revealed enzymes in most of the cases and some FDA approved drugs were found as structurally similar analogs for Trifolin and Yohimbine. These findings could lead to the development of novel and effective anti-angiogenic agents.Communicated by Ramaswamy H. Sarma.

Virtual screening reveals liquiritigenin as a broad-spectrum inhibitor of SARS-CoV-2 variants of concern: an in silico study.

The SARS-CoV-2 has severely impacted the lives of people worldwide. Global concern is on the rise due to a large number of unexpected mutations in the viral genome, resulting in new variants. Nature-based bioactive phytochemicals hold great promise as inhibitors against pathogenic viruses. The current study was aimed at evaluating some bioactive antiviral phytochemicals against SARS-CoV-2 variants of concern. A total of 46 phytochemicals were screened against the pathogenic spike protein of Alpha, Beta, Delta, Gamma, and Omicron variants. In addition to molecular docking, screening for favorable pharmacokinetic and pharmacodynamic properties such as absorption, distribution, metabolism, excretion, and toxicity was undertaken. For each of the aforementioned five SARS-CoV-2 variants of concern, a 100 ns molecular dynamics simulation was run to assess the stability of the complexes between their respective spike protein receptor-binding domain and the best-selected compound. From our current investigation, the natural compound liquiritigenin turned out to be the most promising potential lead compound against almost all the variants. These findings could pave the way for the development of effective medications against SARS-CoV-2 variants. However, in vivo trials in future studies are necessary for further validation of our results.Communicated by Ramaswamy H. Sarma.

Core Proteomics and Immunoinformatic Approaches to Design a Multiepitope Reverse Vaccine Candidate against Chagas Disease.

Chagas disease is a tropical ailment indigenous to South America and caused by the protozoan parasite Trypanosoma cruzi, which has serious health consequences globally. Insect vectors transmit the parasite and, due to the lack of vaccine availability and limited treatment options, we implemented an integrated core proteomics analysis to design a reverse vaccine candidate based on immune epitopes for disease control. Firstly, T. cruzi core proteomics was used to identify immunodominant epitopes. Therefore, we designed the vaccine sequence to be non-allergic, antigenic, immunogenic, and to have better solubility. After predicting the tertiary structure, docking and molecular dynamics simulation (MDS) were performed with TLR4, MHC-I, and MHC-II receptors to discover the binding affinities. The final vaccine design demonstrated significant hydrogen bond interactions upon docking with TLR4, MHC-I, and MHC-II receptors. This indicated the efficacy of the vaccine candidate. A server-based immune simulation approach was generated to predict the efficacy. Significant structural compactness and binding stability were found based on MDS. Finally, by optimizing codons on Escherichia coli K12, a high GC content and CAI value were obtained, which were then incorporated into the cloning vector pET2+ (a). Thus, the developed vaccine sequence may be a viable therapy option for Chagas disease.