Identification of potential riboflavin synthase inhibitors by virtual screening and molecular dynamics simulation studies

Riboflavin synthase is an important enzyme catalyzing the last step of riboflavin biosynthesis in microorganisms. Due to the absolute dependency of the microbes to this biosynthetic pathway coupled with its nonexistence in humans, riboflavin synthase (RiS) is considered as a prospective drug target. The riboflavin synthase for this study was derived from Leptospira kmetyi, a pathogenic bacterium locally isolated in Malaysia. Leptospirosis, an infectious disease caused by pathogenic Leptospira, is a serious growing public health issue. Treatment of leptospirosis with antibiotics over time resulted in the evolution of antibiotic resistance strains, thus requiring the development of newer but safe antimicrobial agents. In this study, a computational approach involving virtual screening followed by molecular dynamics (MD) simulation was implemented in order to identify possible inhibitors against riboflavin synthase. The model of Leptospira kmetyi riboflavin synthase predicted from E. coli riboflavin synthase (1I8D) was used as the drug target to screen for potential compounds from the ZINC database through virtual screening. The potential compound with the highest Glide score (−10.987 Kcal/mol) was identified to be ZINC21883831. Chemically it is 2-[(2-chloro-4-fluoro-phenyl)methylsulfanyl]-7-phenyl-3,5-dihydropyrrolo[2,3-e]pyrimidin-4-one. The top three docked complexes from the virtual screening and apo-structures were subjected to molecular dynamics simulation to predict the stabilities of the Leptospira kmetyi riboflavin synthase-ligand complexes. Stability parameters including RMSD, RMSF, SASA and Rg of the complexes were evaluated from 60 ns of the MD simulation trajectories. Insights from this study provide promising starting points for the rational designs of new effective and safe anti-leptospirosis drugs

Discovery of a new class of inhibitors for the protein arginine deiminase type 4 (PAD4) by structure-based virtual screening

<p>Abstract</p> <p>Background</p> <p>Rheumatoid arthritis (RA) is an autoimmune disease with unknown etiology. Anticitrullinated protein autoantibody has been documented as a highly specific autoantibody associated with RA. Protein arginine deiminase type 4 (PAD4) is the enzyme responsible for catalyzing the conversion of peptidylarginine into peptidylcitrulline. PAD4 is a new therapeutic target for RA treatment. In order to search for inhibitors of PAD4, structure-based virtual screening was performed using LIDAEUS (Ligand discovery at Edinburgh university). Potential inhibitors were screened experimentally by inhibition assays.</p> <p>Results</p> <p>Twenty two of the top-ranked water-soluble compounds were selected for inhibitory screening against PAD4. Three compounds showed significant inhibition of PAD4 and their IC₅₀values were investigated. The structures of the three compounds show no resemblance with previously discovered PAD4 inhibitors, nor with existing drugs for RA treatment.</p> <p>Conclusion</p> <p>Three compounds were discovered as potential inhibitors of PAD4 by virtual screening. The compounds are commercially available and can be used as scaffolds to design more potent inhibitors against PAD4.</p

Adsorption and desorption properties of total flavonoids from oil palm (Elaeis guineensis Jacq.) mature leaf on macroporous adsorption resins

Three different macroporous resins (XAD7HP, DAX-8, and XAD4) were evaluated for their adsorption and desorption properties in preparing flavonoid-enriched oil palm (Elaeis guineensis Jacq.) leaf extract. The influences of initial concentration, solution pH, contact time, and desorption solvent (ethanol) concentration were determined by static sorption/desorption methods. The optimal condition for adsorption of flavonoids was achieved when the solution of the extract was adjusted to pH 7, reaching equilibrium after 1440 min at 298 K. The adsorption process was well described by a pseudo-second-order kinetics model, while the adsorption isotherm data fitted well with a Freundlich model. The adsorption by each resin was via an exothermic and physical adsorption process. Based on the static experiment results, XAD7HP was found to be the most appropriate adsorbent, while 80% ethanol was the best solvent for desorbent. Further evaluation of its dynamic adsorption and desorption characteristics on a packed glass column showed that XAD7HP could enrich the OPL total flavonoid content by a 3.57-fold increment. Moreover, UHPLC–UV/PDA and UHPLC–MS/MS analysis revealed that apigenin and luteolin derivatives were selectively adsorbed by XAD7HP. Additionally, both the crude OPL extract and the flavonoid-enriched fraction have good DPPH and NO free radical scavenging activities. Multiple interactions between the flavonoids and cross-linked polymeric XAD7HP resin through van der Waals forces and hydrogen bonding described the sorption processes. Therefore, by utilizing this method, the flavonoid-enriched fraction from crude OPL extract could be used as a potential bioactive ingredient in nutraceutical and pharmaceutical applications at minimum cost with optimum efficiency

A synchrotron X-ray imaging strategy to map large animal brains

Mapping the large neural networks of animal and human brains is a fundamental but so far elusive task, because of the massive amount of data and the consequent prohibitively long image taking and processing times. We developed an effective strategy called "AXON" (Accelerated X-ray Observation of Neurons) to solve this problem. AXON can achieve comprehensive whole-brain mapping within a reasonable time by combining fast image taking and processing, plus two other critical performances: three-dimensional (3D) imaging with high and isotropic spatial resolution, and multi-scale resolution. We successfully tested this strategy with coordinated experiments at four synchrotron facilities in Japan, Taiwan, Singapore and Korea on two animal models, Drosophila and mouse. Its performances notably allowed full 3D mapping of the Drosophila brain in a few days. With reasonable improvements, AXON can deliver full mapping of large animal and human brains on a realistic time scale of a few years