Objectives Acute pancreatitis (AP) is an inimical disorder associated with overall mortality rates between 10-15%. It is a disorder of the exocrine pancreas which is characterized by local and systemic inflammatory responses primarily driven by oxidative stress and death of pancreatic acinar cells. The severity of AP ranges from mild pancreatic edema with complete recuperative possibilities to serious systemic inflammatory response resulting in peripancreatic/pancreatic necrosis, multiple organ failure, and death. Key findings We have retrieved the potential alternative approaches that are developed lately for efficacious treatment of AP from the currently available literature and recently reported experimental studies. This review summarizes the need for alternative approaches and combinatorial treatment strategies to deal with AP based on literature search using specific key words in PubMed and ScienceDirect databases. Summary Since AP results from perturbations of multiple signaling pathways, the so called "monotargeted smart drugs" of the past decade is highly unlikely to be effective. Also, the conventional treatment approaches were mainly involved in providing palliative care instead of curing the disease. Hence, many researchers are beginning to focus on developing alternate therapies to treat AP effectively. This review also summarizes the recent trends in the combinatorial approaches available for AP treatment.Current pharmacological approaches for AP Vaishnavi Sundar et al.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions and has killed millions to date. Studies are being carried out to find therapeutic molecules that can potentially inhibit the replication of SARS-CoV-2. 3-chymotrypsin-like protease (3CL pro) involved in the polyprotein cleavage process is believed to be the key target for viral replication, and hence is an attractive target for the discovery of antiviral molecules. In the present study, we aimed to identify natural phytocompounds from Bridelia retusa as potential inhibitors of SARS-CoV-2 3CL pro (PDB ID: 6M2N) using in silico techniques. Molecular docking studies conducted with three different tools in triplicates revealed that ellagic acid (BR6) and (+)-sesamin (BR13) has better binding affinity than the co-crystal inhibitor “3WL” of 6M2N. BR6 and BR13 were found to have a high LD 50 value with good bioavailability. 3WL, BR6, and BR13 bind to the same active binding site and interacted with the HIS41-CYS145 catalytic dyad including other crucial amino acids. Molecular dynamics simulation studies revealed stability of protein–ligand complexes as evidenced from root-mean-square deviations, root-mean-square fluctuations (RMSF), protein secondary structure elements, ligand-RMSF, protein–ligand contacts, ligand torsions, and ligand properties. BR6 (−22.3064 kcal/mol) and BR13 (−19.1274 kcal/mol) showed a low binding free energy value. The Bayesian statistical model revealed BR6 and BR13 as better protease inhibitors than 3WL. Moreover, BR6 and BR13 had already been reported to elicit antiviral activities. Therefore, we conclude that ellagic acid and (+)-sesamin as natural antiviral phytocompounds with inhibitory potential against SARS-CoV-2 3CL pro. Supplementary information The online version contains supplementary material available at 10.1007/s11224-022-01959-3.

G-protein-coupled receptors (GPCRs) have evolved as highly specialized cellular machinery that can dictate biological outcomes in response to diverse stimuli. Specifically, they induce multiple pathway responses upon structural perturbations induced at local protein sites. GPCRs utilize a concurrent strategy involving a central transmembrane topology and biochemical modifications for precise functional implementation. However, the specific role of the latter is not known due to the lack of precise probing techniques that can characterize receptor dynamics upon biochemical modifications. Phosphorylation is known to be one of the critical biochemical modifications in GPCRs that aids in receptor desensitization via arrestin binding. Here, we carry out all-atom molecular dynamics simulations of rhodopsin in a membrane environment to study its conformational dynamics induced upon phosphorylation. Interestingly, our comparative analysis of non-phosphorylated and phosphorylated rhodopsin structure demonstrated enhanced receptor stability upon phosphorylation at the C-terminal region that leads to the opening of the extracellular part of the transmembrane helices. In addition, monitoring the distinct number of phosphorylation states showed that having fewer phosphorylated residues does not bring about appropriate conformational changes in the extracellular region. Since phosphorylation results in receptor desensitization and recycling of the ligand, our findings provide significant insights into the conformational dynamics of the mechanism of ligand exit from the receptor.

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