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In last two decades, the world has seen an exponential increase in the antimicrobial resistance (AMR), making the issue a serious threat to human health. The mortality caused by AMR is one of the leading causes of human death worldwide. Till the end of the twentieth century, a tremendous success in the discovery of new antibiotics was seen, but in last two decades, there is negligible progress in this direction. The increase in AMR combined with slow progress of antibiotic drug discovery has created an urgent demand to search for newer methods of intervention to combat infectious diseases. One of such approach is to look for biofilm and quorum sensing (QS) inhibitors. Plants are excellent source of wide class compounds that can be harnessed to look for the compounds with such properties. This study proves a broad-spectrum biofilm and QS inhibitory potential of umbelliferone. More than 85% reduction in violacein production Chromobacterium violaceum 12472 was found. All tested virulent traits of Pseudomonas aeruginosa PAO1 and Serratia marcescens MTCC 97 were remarkably inhibited that ranged from 56.62% to 86.24%. Umbelliferone also successfully prevented the biofilm of test bacteria at least by 67.68%. Umbelliferone interacted at the active site of many proteins of QS circuit, which led to the mitigation of virulent traits. The stable nature of complexes of umbelliferone with proteins further strengthens in vitro results. After examining the toxicological profile and other drug-like properties, umbelliferone could be potentially developed as new drug to target the infections caused by Gram - ve bacteria.Communicated by Ramaswamy H. Sarma.

Antimicrobial resistance poses a significant challenge to public health, especially in developing countries, due to a substantial rise in bacterial resistance. This situation has become so concerning that we are now at risk of losing the effectiveness of antibiotics altogether. Recent research has firmly established that bacteria engage in a process called quorum sensing (QS). QS regulates various functions, including nutrient scavenging, immune response suppression, increased virulence, biofilm formation and mobility. Pseudomonas aeruginosa , an opportunistic bacterial pathogen, plays a significant role in various medical conditions such as chronic wounds, corneal infections, burn wounds and cystic fibrosis. While antibiotics are effective in killing bacteria, only a few antibiotics, particularly those from the β-lactam group, have been studied for their impact on the quorum sensing of P. aeruginosa . Given the lack of concentrated efforts in this area, we have investigated the role of β-lactam antibiotics on various potential targets of P. aeruginosa . Based on their toxicological profiles and the average binding energy obtained through molecular docking, azlocillin and moxalactam have emerged as lead antibiotics. The binding energy for the docking of azlocillin and moxalactam with LasA was determined to be -8.2 and -8.6 kcal/mol, respectively. Molecular simulation analysis has confirmed the stable interaction of both these ligands with all three target proteins (LasI, LasA and PqsR) under physiological conditions. The results of this research underscore the effectiveness of azlocillin and moxalactam. These two antibiotics may be repurposed to target the quorum sensing of P. aeruginosa .Communicated by Ramaswamy H. Sarma.

A respiratory pandemic known as coronavirus disease-19 (COVID-19) has created havoc since it emerged from Wuhan, China. COVID-19 is caused by a newly emerged SARS coronavirus (SARS-CoV) with increased pathogenicity named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Due to the lack of understanding of the mechanism of pathogenesis, an effective therapeutic option is unavailable. Epidemics described in Unani ancient literature include nazla-e-wabai and humma-e-wabai , and most of the symptoms of COVID-19 resemble nazla-e-wabai . Hence, in light of Unani literature, the treatment of COVID-19 can be managed with the composites prescribed in Unani medicine for nazla-e-wabai . In this study, a structure-based drug design approach was carried out to check the effectiveness of the pharmacologically active constituents of the Unani composites prescribed to treat nazla-e-wabai against SARS-CoV-2. We performed molecular docking of the active constituents of these composites against the main protease (M pro ), a potential drug target in SARS-CoV-2. Using detailed molecular docking analysis, Habb-ul-aas and Tabasheer were identified as potential inhibitors of SARS-CoV-2 M pro . The active constituents of both these composites bind to the substrate-binding pocket of SARS-CoV-2 M pro , forming interactions with key residues of the binding pocket. Molecular dynamics (MD) simulation suggested the binding of active constituents of Habb-ul-aas with SARS-CoV-2 M pro with a strong affinity as compared to the constituents of Tabasheer. Thus, this study sheds light on the use of these Unani composites in COVID-19 therapeutics.Communicated by Ramaswamy H. Sarma.

Donepezil is an acetylcholinesterase inhibitor (AChEI) in use to treat symptomatic patients of mild to moderate Alzheimer's disease (AD). Ferritin is an iron protein associated with storage and sequestration of excess ferrous iron in a way maintaining proper function of cellular processes and plays a key role in AD since steady-state dysregulation of metal ion metabolism in vivo is associated with AD pathology. In lieu of therapeutics importance of ferritin and donepezil in AD, this study aims at investigating the binding between these two employing molecular docking and molecular dynamics (MD) simulation. In this study, we performed structure-based docking of donepezil with human Ferritin. Primarily, the top pose based on the binding affinity was selected and then interaction analysis was carried out to find the stable pose. Structural annotations by docking analysis were further accompanied by all-atom MD simulation for 100 ns followed by principal component and free energy landscape analyses to investigate the conformational changes, stability, and interaction mechanism of ferritin with donepezil. MD simulation suggested that the binding of donepezil stabilizes the ferritin structure and leads to fewer conformational changes. This study gives an insight at the atomistic level into the interaction between donepezil and ferritin thereby aiding in understanding the activity and mechanism of protein and drug binding. The study is clinically significant as iron participates in the occurrence of AD.

The unavoidable glycation reaction is the major cause of diabetes and metabolic disorders. The glycation reaction is enhanced in case when the glycating agent is reactive carbonyl species (RCS) like, methylglyoxal (MG). The impact of RCS may result into the diabetes mellitus and its secondary complications along-with its role in cancers too. This reaction can be discontinued by using natural product inhibitors or by chemically synthesized drugs, like aminoguanidine (AG). However, AG is reported to be nephrotoxic (toxic to kidneys) at a concentration of 10 mM or more and has therefore serious health concerns. In the present study, bioconjugation of AG was done with the gold nanoparticles (Gnps) to mitigate its toxic effect and upsurge the efficacy of AG on RCS induced glycation. The AG-Gnps formed waas characterized by UV-Vis. spectroscopy and it reveals a peak at 529 nm corresponding to AG-gold nanoparticles. The particle size of the AG-Gnp was found to be 12 nm in TEM while in DLS it was found to be 54.07 nm. The fluorescence studies in combination with GK-peptide and δ-Glu assay support the inhibition of AGEs by AG-Gnps. Based on the idea of gold nano-particle synthesis, it is anticipated, the toxicity of numerous drugs used at high doses can be diminished with additional efficiency.Communicated by Ramaswamy H. Sarma.

Methylglyoxal (MG) is a potent glycating agent which reacts with proteins to form advanced glycation end products (AGEs). These chemically stable AGEs crosslink with proteins and could lead to amyloid formation that has the role in several diseases including Alzheimer's and Parkinson's. In this piece of work, glycation-induced conformational changes in HSA were observed with quenching of tryptophan fluorescence by 73.8% (41 nm red shift) and loss of hydrophobicity of HSA. CD spectroscopy result reaffirmed secondary structure changes in HSA. Moreover, MG-induced changes in HSA, proceeds to amyloid structure as characterized by an increase in thioflavin (ThT) fluorescence and transmission electron microscopy (TEM) images of HSA aggregates. Quercetin was found to inhibit both AGEs production and amyloid formation. Viability of MCF-7 cells was found to be increased with AGEs treatment, illustrating proliferation of cancer cells. Wound healing assay also revealed increased proliferation and migration of cells in the presence of AGEs. Additionally, molecular docking analyses were performed to demonstrate interactions involved in the stabilization of HSA-quercetin complex. The binding affinities of quercetin were found to be ( K d = 10 5 M -1 ) much higher compared with MG ( K d = 10 2 M -1 ). From this study, it is quite clear that quercetin reverses the effect of MG by sterically inhibiting the interaction between HSA and MG. Communicated by Ramaswamy H. Sarma.

Carbendazim is a benzimidazole fungicide used to control the fungal invasion. However, its exposure might lead to potential health problems. The present study evaluates the interaction of carbendazim (CAR) with human serum albumin (HSA) which is an important drug carrier protein and plays a very crucial role in the transportation of small molecules. A number of biophysical techniques were employed to investigate the binding of CAR with HSA. The increased UV-absorption of HSA on titrating with CAR suggests the formation of HSA-CAR complex and it could be due to the exposure of aromatic residues. The fluorescence study confirmed that CAR quenches the fluorescence of HSA and showed the static mode of quenching. CAR (50 µM) quenches around 56.14% of the HSA fluorescence. The quenching constant, binding constant, number of binding site and free energy change was calculated by fluorescence quenching experiment. Competitive displacement assay showed Sudlow's site I as the primary binding site of CAR on HSA. The synchronous fluorescence study revealed the perturbation in the microenvironment around tyrosine and tryptophan residues upon binding of CAR to HSA. The circular dichroism results suggested that the binding of CAR to HSA altered its secondary structure. Molecular docking experiment demonstrated the binding of CAR to Sudlow's site I of HSA. Docking studies suggested that the hydrogen bonding, van der Waals and pi-alkyl are playing role in the interaction of CAR with HSA. The study confirmed the conformational changes within HSA upon binding of CAR.