Aggregation of amyloid beta (Aβ) protein considered as one of contributors in development of Alzheimer's disease (AD). Several investigations have identified the importance of non-steroidal anti-inflammatory drugs (NSAIDs) as Aβ aggregation inhibitors. Here, we have examined the binding interactions of 24 NSAIDs belonging to eight different classes, with Aβ fibrils by exploiting docking and molecular dynamics studies. Minimum energy conformation of the docked NSAIDs were further optimized by density functional theory (DFT) employing Becke's three-parameter hybrid model, Lee-Yang-Parr (B3LYP) correlation functional method. DFT-based global reactivity descriptors, such as electron affinity, hardness, softness, chemical potential, electronegativity, and electrophilicity index were calculated to inspect the expediency of these descriptors for understanding the reactive nature and sites of the molecules. Few selected NSAID-Aβ fibrils complexes were subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. All of the NSAIDs exhibited potential activity against Aβ fibrils in terms of predicted binding affinity. Sulindac was found to be the most active compound underscoring the contribution of indene methylene substitution, whereas acetaminophen was observed as least active NSAID. General structural requirements for interaction of NSAIDs with Aβ fibril include: aryl/heteroaryl aromatic moiety connected through a linker of 1-2 atoms to a distal aromatic group. Considering these structural requirements and electronic features, new potent agents can be designed and developed as potential Aβ fibril inhibitors for the treatment of AD.

Ivermectin (IVM) is a broad-spectrum antiparasitic agent, having inhibitory potential against wide range of viral infections. It has also been found to hamper SARS-CoV-2 replication in vitro, and its precise mechanism of action against SARS-CoV-2 is yet to be understood. IVM is known to interact with host importin (IMP)α directly and averts interaction with IMPβ1, leading to the prevention of nuclear localization signal (NLS) recognition. Therefore, the current study seeks to employ molecular docking, molecular mechanics generalized Born surface area (MM-GBSA) analysis and molecular dynamics simulation studies for decrypting the binding mode, key interacting residues as well as mechanistic insights on IVM interaction with 15 potential drug targets associated with COVID-19 as well as IMPα. Among all COVID-19 targets, the non-structural protein 9 (Nsp9) exhibited the strongest affinity to IVM showing −5.30 kcal/mol and −84.85 kcal/mol binding energies estimated by AutoDock Vina and MM-GBSA, respectively. However, moderate affinity was accounted for IMPα amounting −6.9 kcal/mol and −66.04 kcal/mol. Stability of the protein-ligand complexes of Nsp9-IVM and IMPα-IVM was ascertained by 100 ns trajectory of all-atom molecular dynamics simulation. Structural conformation of protein in complex with docked IVM exhibited stable root mean square deviation while root mean square fluctuations were also found to be consistent. In silico exploration of the potential targets and their interaction profile with IVM can assist experimental studies as well as designing of COVID-19 drugs. Communicated by Ramaswamy H. Sarma

Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short −CH2– linker displayed promising antimycobacterial activity, with the imidazole–CH2– series (7) showing low MIC values (6.25–25 μg/mL), which was also influenced by lipophilicity. Extending the linker to −C(O)NH(CH2)2– resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV–visible optical titrations with KD values of 2.63, 35.6, and 290 μM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.

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