A discovery of potent kaempferol derivatives as multi-target medicines against diabetes as well as bacterial infections: an in silico approach.

Flavonoids demonstrate beneficial effects on human health because flavonoids contain important biological properties. Kaempferol is a flavonol, type of flavonoid found in eatable plants and in plants usually employed in ancient drugs (Moringa oleifera, Tilia spp., fern genus spp. and gingko etc.). Some medicinal studies have shown that the use of foods full of kaempferol decreases the risk of many (cancer, vascular) diseases. All the data of 50 kaempferol derivatives were collected from PubChem database. Through Schrödinger software, 3D-QSAR study was performed for 50 compounds by using method of field base. Conformer of kaempferol derivatives was docked against anti-diabetic, anti-microbial co-crystal structures and protein. To monitor the best anti-diabetic and antibacterial agent, particular kaempferol derivatives were downloaded from PubChem database. Virtual screening by molecular docking provided four lead compounds with four different proteins. These hit compounds were found to be potent inhibitor for diabetic enzymes alpha-amylase and DPP IV and had the potential to suppress DNA gyrase and dihydrofolate reductase synthesis. Molecular dynamic simulation of docked complexes evaluates the value of root mean square fluctuation by iMOD server. Kaempferol 3-O-alpha-L-(2, 3-di-Z-p-coumaroyl) rhamnoside (42) compound used as anti-diabetic and kaempferol 3-O-gentiobioside (3) as antibacterial with good results can be used for drug discovery.Communicated by Ramaswamy H. Sarma.

Novel computational and drug design strategies for the inhibition of human T-cell leukemia virus 1-associated lymphoma by Astilbin derivatives.

Human T-cell leukemia virus 1 (HTLV-1) associated lymphoma is a devastating malignancy triggered by HTLV-1 infections. We employeda comprehensive drug design and computational strategy in this work to explore the inhibitory activitiesof Astilbin derivatives against HTLV-1-associated lymphoma. We evaluated the stability, binding affinities, and various computational analysis of Astilbin derivatives against target proteins, such as HTLV-1 main protease and HTLV-1 capsid protein. The root mean square deviation (RMSD), root mean square fluctuation, radius of gyration, hydrogen bond analysis, principal component analysis (PCA) and dynamic cross-correlation matrix (DCCM) were applied to characterize these protein-ligand interactions further. Ligand-03 and ligand-04 exhibited notable binding affinity to HTLV-1 capsid protein, while ligand-05 displayed high binding affinity to HTLV-1 protease. MD simulation analysis revealed that ligand-03, bound to HTLV-1 capsid protein, demonstrated enhanced stability with lower RMSD values and fewer conformational changes, suggesting a promising binding orientation. Ligand-04, despite stable binding, exhibited increased structural deviations, making it less suitable. Ligand-05 demonstrated stable binding to HTLV-1 protease throughout the simulation period at 100 nanoseconds. Hydrogen bond analysis indicated that ligand-05 formed persistent hydrogen bonds with significantresidues, contributing to its stability. PCA highlighted ligand-03's more remarkable conformational changes, while DCCM showed ligand-05's distinct dynamics, indicating its different behavior in the complex. Furthermore, binding free energy calculations supported the favorable interactions of ligand-03 and ligand-04 with HTLV-1 capsid protein, while ligand-05 showed weaker interactions with HTLV-1 protease. Molecular electrostatic potential and frontier molecular orbital analyses provided insights into these compounds' charge distribution and stability. In conclusion, this research found Astilbin derivatives as potential inhibitors of HTLV-1-associated lymphoma. Future attempts at drug development will benefit from the steady interaction landscape provided by Ligand-03, Ligand-04 and Ligand-05, which showed the most attractive binding profile with the target protein. These results open up new opportunities for innovative drug development, and more experimental testing should be done between Astilbin derivatives and HTLV-1-associated lymphoma.Communicated by Ramaswamy H. Sarma.

Integrating virtual screening, pharmacoinformatics profiling, and molecular dynamics: identification of promising inhibitors targeting 3CLpro of SARS-CoV-2.

Introduction: The pursuit of effective therapeutic solutions for SARS-CoV-2 infections and COVID-19 necessitates the repurposing of existing compounds. This study focuses on the detailed examination of the central protease, 3-chymotrypsin-like protease (3CLpro), a pivotal player in virus replication. The combined approach of molecular dynamics simulations and virtual screening is employed to identify potential inhibitors targeting 3CLpro. Methods: A comprehensive virtual screening of 7120 compounds sourced from diverse databases was conducted. Four promising inhibitors, namely EN1036, F6548-4084, F6548-1613, and PUBT44123754, were identified. These compounds exhibited notable attributes, including high binding affinity (ranging from -5.003 to -5.772 Kcal/mol) and superior Induced Fit Docking scores (ranging from -671.66 to -675.26 Kcal/mol) compared to co-crystallized ligands. Results: In-depth analysis revealed that F6548-1613 stood out, demonstrating stable hydrogen bonds with amino acids His41 and Thr62. Notably, F6548-1613 recorded a binding energy of -65.72 kcal/mol in Molecular Mechanics Generalized Born Surface Area (MMGBSA) simulations. These findings were supported by Molecular Dynamics simulations, highlighting the compound's efficacy in inhibiting 3CLpro. Discussion: The identified compounds, in compliance with Lipinski's rule of five and exhibiting functional molecular interactions with 3CLpro, present promising therapeutic prospects. The integration of in silico methodologies significantly expedites drug discovery, laying the foundation for subsequent experimental validation and optimization. This approach holds the potential to develop effective therapeutics for SARS-CoV-2.