RESUMEN
Indiscriminate use of anti-microbial agents has resulted in the inception, frequency, and spread of antibiotic resistance among targeted bacterial pathogens and the commensal flora. Mur enzymes, playing a crucial role in cell-wall synthesis, are one of the most appropriate targets for developing novel inhibitors against antibiotic-resistant bacterial pathogens. In the present study, in-silico high-throughput virtual (HTVS) and Standard-Precision (SP) screening was carried out with 0.3 million compounds from several small-molecule libraries against the E. coli Mur D enzyme (PDB ID 2UUP). The docked complexes were further subjected to extra-precision (XP) docking calculations, and highest Glide-score compound was further subjected to molecular simulation studies. The top six virtual hits (S1-S6) displayed a glide score (G-score) within the range of -9.013 to -7.126 kcal/mol and compound S1 was found to have the highest stable interactions with the Mur D enzyme (2UUP) of E. coli. The stability of compound S1 with the Mur D (2UUP) complex was validated by a 100-ns molecular dynamics simulation. Binding free energy calculation by the MM-GBSA strategy of the S1-2UUP (Mur D) complex established van der Waals, hydrogen bonding, lipophilic, and Coulomb energy terms as significant favorable contributors for ligand binding. The final lead molecules were subjected to ADMET predictions to study their pharmacokinetic properties and displayed promising results, except for certain modifications required to improve QPlogHERG values. So, the compounds screened against the Mur D enzyme can be further studied as preparatory points for in-vivo studies to develop potential drugs. HIGHLIGHTSE.coli is a common cause of urinary tract infections.E.coli MurD enzyme is a suitable target for drug development.Novel inhibitors against E.coli MurD enzyme were identified.Molecular dynamics studies identified in-silico potential of identified compound.ADMET predictions and Lipinski's rule of five studies showed promising results.Communicated by Ramaswamy H. Sarma.
RESUMEN
Canthaxanthin is an orange-red keto-carotenoid that occurs naturally and is also manufactured by synthetic methods for regular applications. In nature, canthaxanthin mainly exists in microbes such as different bacterial species, fungi, and algae, as well as in animals such as crustaceans, certain fishes, and birds. However, the amount of canthaxanthin produced in these organisms varies significantly. Additionally, the compound can be generated from genetically modified organisms using genetic engineering techniques Canthaxanthin finds extensive application as an additive in animal feed, in the pharmaceutical industry, as a coloring agent for various food products, and in cosmetics. It has powerful antioxidant properties and plays a role in lipid metabolism, neuroprotection, and immunomodulation. This article gives an extensive insight into the structure and methods of synthesis of canthaxanthin along with its various newly discovered sources identified so far. The significant applications of canthaxanthin, particularly its role in pharmaceuticals, are critically evaluated. Furthermore, the article discusses future aspects and challenges associated with canthaxanthin production and regulation.
RESUMEN
Introduction: The rapid emergence of antibiotic resistance among various bacterial pathogens has been one of the major concerns of health organizations across the world. In this context, for the development of novel inhibitors against antibiotic-resistant bacterial pathogens, UDP-N-Acetylmuramoyl-L-Alanine-D-Glutamate Ligase (MurD) enzyme represents one of the most apposite targets. Body: The present review focuses on updated advancements on MurD-targeted inhibitors in recent years along with genetic regulation, structural and functional characteristics of the MurD enzyme from various bacterial pathogens. A concise account of various crystal structures of MurD enzyme, submitted into Protein Data Bank is also discussed. Discussion: MurD, an ATP dependent cytoplasmic enzyme is an important target for drug discovery. The genetic organization of MurD enzyme is well elucidated and many crystal structures of MurD enzyme are submitted into Protein Data bank. Various inhibitors against MurD enzyme have been developed so far with an increase in the use of in-silico methods in the recent past. But cell permeability barriers and conformational changes of MurD enzyme during catalytic reaction need to be addressed for effective drug development. So, a combination of in-silico methods along with experimental work is proposed to counter the catalytic machinery of MurD enzyme.