Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. Using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

BACKGROUND: Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. AIM: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. METHODS: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. RESULTS: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. CONCLUSION: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Identification of synthetically tractable MERS-CoV main protease inhibitors using structure-based virtual screening and molecular dynamics potential of mean force (PMF) calculations.

The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is a potentially lethal infection that presents a substantial threat to health, especially in Middle East nations. Given that no FDA-approved specific therapy for MERS infection exists, designing and discovering a potent antiviral therapy for MERS-CoV is crucial. One pivotal strategy for inhibiting MERS replication is to focus on the viral main protease (Mpro). In this study, we identify potential novel Mpro inhibitors employing structure-based virtual screening of our recently reported Ugi reaction-derived library (URDL) consisting of cherry-picked molecules from the literature. The key features of the URDL library include synthetic tractability (1-2 pot synthesis) of the molecules scaffold and unexplored chemical space. The hits were ranked based on the docking score, MM-GBSA free energy of binding, and the interaction pattern with the active site residues. A molecular dynamics (MD) simulation study was performed for the first two top-ranked compounds to analyze the stability and free binding energy based on the molecular mechanics Poisson-Boltzmann surface area. The potential mean force calculated from the steered molecular dynamics (SMD) simulations of the hits indicates improved H-bond potential, enhanced conformational stability, and binding affinity toward the target, compared to the cocrystallized ligand. The discovered hits represent novel synthetically tractable scaffolds as potential MERS-CoV Mpro inhibitors.Communicated by Ramaswamy H. Sarma.

Indene-Derived Hydrazides Targeting Acetylcholinesterase Enzyme in Alzheimer's: Design, Synthesis, and Biological Evaluation.

As acetylcholinesterase (AChE) plays a crucial role in advancing Alzheimer's disease (AD), its inhibition is a promising approach for treating AD. Sulindac is an NSAID of the aryl alkanoic acid class, consisting of a indene moiety, which showed neuroprotective behavior in recent studies. In this study, newer Indene analogs were synthesized and evaluated for their in vitro AChE inhibition. Additionally, compared with donepezil as the standard drug, these Indene analogs were accessed for their cell line-based toxicity study on SH-SY5Y cell line. The molecule SD-30, having hydrogen bond donor (HBD) at para-position, showed maximum AChE inhibition potential (IC50 13.86 ± 0.163 µM) in the indene series. Further, the SD-30 showed maximum BuChE inhibition potential (IC50 = 48.55 ± 0.136 µM) with a selectivity ratio of 3.50 and reasonable antioxidant properties compared to ascorbic acid (using DPPH assay). SD-30 (at a dose level: of 10 µM, 20 µM) effectively inhibited AChE-induced Aß aggregation and showed no significant toxicity up to 30 mM against SH-SY5Y cell lines.