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Aggregation of amyloid beta (Aβ) peptides leads to formation of fibrilar, soluble oligomers, and their deposition is a key event in progression of Alzheimer’s disease (AD). Recent experimental studies of Arg-Arg-7-amino-4-trifluoromethylcoumarin (RR-AFC) showed significant Aβ aggregation inhibition, but its molecular mechanism is not yet clear. Hence, the present study aims at exploring the underlying mechanism of destabilization and inhibition of aggregation of the Aβ protofibril by RR-AFC at the molecular level. Molecular docking analysis shows that RR-AFC binds to chain A of the Aβ protofibril through hydrogen bonding interactions. Comparative molecular dynamics simulations depict the binding of RR-AFC at the edge of chain A, and its partially inserted conformation at the hydrophobic core destabilizes the Aβ protofibril. Its binding causes loss of hydrophobic contacts, leading to a partial opening of tightly packed β-sheet protofibrils. The hydration effect of salt bridge between the amino group of Lys28 and the oxygen atom of RR-AFC contributes in destabilization of Aβ protofibrils. Binding free energy calculations of RR-AFC and the Aβ protofibril showed that van der Waals interactions are dominant over the others. Thus, our results revealed that RR-AFC interacts mainly with the hydrophobic core along with positively charged residues of the Aβ protofibril for effective destabilization. Thus, this structural information could be useful to design new inhibitors to control the aggregation of Aβ protofibrils in AD patients.

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Bacillus velezensis SK having broad-spectrum antimicrobial activity has been isolated from soil. The efficient extraction of antimicrobial compounds produced in various mediums has been done using Diaion HP-20 resin. Further, characterization of an antimicrobial compound by TLC, FTIR, in-situ bioautography analysis revealed the presence of cyclic lipopeptides, which is then purified by the combination of silica gel, size exclusion, dual gradient, and RP-HPLC chromatography techniques. Growth kinetic studies showed that Bacillus velezensis SK produces a mixture of lipopeptides (1.33 gL−1). The lipopeptide exhibits good pH (2–10) and temperature stability up to 80 °C. LC–ESI–MS analysis of partially purified lipopeptide identified variant of surfactin, further analysis of purified chromatographic fractions revealed the occurrence of most abundant C15-surfactin homologues (m/z 1036.72 Da). The isolated surfactin exhibits good antimicrobial activity (1600 AU/ml) against drug-resistant food-born B. cereus and human pathogen Staphylococcus aureus. Hence, identified strain B. velezensis SK and its potent antibacterial surfactin lipopeptide could be used in various food and biomedical applications.

In the landscape of epigenetic regulation, histone deacetylase 3 (HDAC3) has emerged as a prominent therapeutic target for the design and development of candidate drugs against various types of cancers and other human disorders. Herein, we have performed ligand-based pharmacophore modeling, virtual screening, molecular docking, and MD simulations to design potent and selective inhibitors against HDAC3. The predicted best pharmacophore model ‘Hypo 1’ showed excellent correlation (R2 = 0.994), lowest RMSD (0.373), lowest total cost value (102.519), and highest cost difference (124.08). Hypo 1 consists of four salient pharmacophore features viz. one hydrogen bond acceptor (HBA), one ring aromatic (RA), and two hydrophobic (HYP). Hypo 1 was validated by Fischer's randomization with a 95% of confidence level and the external test set of 60 compounds with a good correlation coefficient (R2 = 0.970). The virtual screening of chemical databases, drug-like properties calculations followed by molecular docking resulted in identifying 22 representative hit compounds. Performed 50 ns of MD simulations on top three hits were retained the salient π-stacking, Zn2+ coordination, hydrogen bonding, and hydrophobic interactions with catalytic residues from the active site pocket of HDAC3. Total binding energy calculated by MM-PBSA showed that the Hit 1 and Hit 2 formed stable complexes with HDAC3 as compared to reference TSA. Further, the PLIP analysis showed a close resemblance between the salient pharmacophore features of Hypo 1 and the presence of molecular interactions in co-crystallized FDA-approved drugs. We conclude that the screened hit compounds may act as potent inhibitors of HDAC3 and further preclinical and clinical studies may pave the way for developing them as effective therapeutic agents for the treatment of different cancers and neurodegenerative disorders.