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Copyright of Problems of Sustainable Development / Problemy Ekorozwoju is the property of Faculty of Environmental Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Mutations in P53 cause a loop unfolding, resulting in loss of activity and finally leading to cancer. One strategically reported way to arrest such oncogenesis is the restoration of tertiary structure as well as the function of mutant P53. In this attempt, we have designed a benzo-pyrazole-based novel ligand starting from a carbazole compound (EYB or PK9324) reported earlier to reinstate such function in mutant P53 (Y220C mutant, PDB: 6GGD). Assuming PK9324 as the template scaffold, de novo technique (Genetic algorithm, eLEA3D) was adopted within the binding pocket of 6GGD and our ligand DLIG1 was designed after several rounds of mutations. Docking and molecular dynamics (MD) simulation revealed significant interactions with key amino acid residues such as Cys220, Asp228, Leu145, Trp146, Val147, Thr150, Pro151, Pro152, Pro222, Pro223, Asp228, and Thr230. Along with sufficient binding stability, the MMGBSA analysis revealed its comparable binding free energy with other reported reference ligands (i.e. PK9324 and PK9318). Similar to these reference ligands, DLIG1 exhibited specificity in binding towards the Y220C mutant rather than towards wild-type P53. Finally, DLIG1 displayed a reorientation of a hydrophobic cavity in Y220C that hinted restoration of electrostatic interactions within the key loops of P53 favoring regain of its function. [ABSTRACT FROM AUTHOR]

Amyloid β (A β) peptide monomers polymerize to form insoluble amyloid fibril aggregates and accumulate as senile plaques which eventually leads to cognitive impairment. Modulating abnormal amyloid aggregation can be considered a therapeutic target for Alzheimer's disease. Recent studies support that Curcumin interferes with larger protein aggregate formation by destabilizing the salt bridge (Asp 23-Lys 28) of A β protein. The chemical library of curcumin derivative with pyrazole, isoxazole, and isothiazole showed considerable binding affinity comparable to that of curcumin. In silico docking studies of the library of the compound, revealed strong binding affinity with A β protein and β -secretase enzyme (BACE1). De novo ligand design coupled with manual pharmacophore mapping of our best-fitting lead revealed another ligand having a potential binding affinity with both A β protein and BACE-1. Both the compounds passed Lipinski's Rule of Five, in silico toxicity testing by admetSAR, and pharmacophore overlaps with Verubecestat, a compound under clinical trial against Alzheimer's disease. MD dynamic simulation study revealed the stability of protein after it binds to our ligand. Secondary structure determination was also done to observe the changes in α and β sheets of the protein with and without ligand binding. Ligand-based drug design was also carried out via pharmacophore mapping and searching the molecules via zinc database. Pyrazole bearing lead has been identified which may act as dual inhibitor of Amyloid β-42 protein and beta secretase enzyme responsible for protein fibrillation. The best ligand (compound 49) with highest docking scores, appropriate drug likeliness and less toxicity was selected as our lead compound and molecular dynamic simulation studies proved the stability of the compound in the α-β transitions of protein. DSSP plots also exhibited that the winner molecule hindered α-helix to β-sheet transition for many residues (seeding zone of β-β dimerization) in the binding pocket. [ABSTRACT FROM AUTHOR]

Acoustic radiation forces have been used to manipulate cells and bacteria in a number of recent microfluidic applications. The net force on a cell has been subject to careful investigation over a number of decades. We demonstrate that the radiation forces also act to deform cells. An ultrasonic standing wave field is created in a 0.1mm glass capillary at a frequency of 7.9 MHz. Using osmotically swollen red-blood cells, we show observable deformations up to an aspect ratio of 1.35, comparable to deformations created by optical tweezing. In contrast to optical technologies, ultrasonic devices are potentially capable of deforming thousands of cells simultaneously. We create a finite element model that includes both the acoustic environment of the cell, and a model of the cell membrane subject to forces resulting from the non-linear aspects of the acoustic field. The model is found to give reasonable agreement with the experimental results, and shows that the deformation is the result of variation in an acoustic force that is directed outwards at all points on the cell membrane. We foresee applications in diagnostic devices, and in the possibility of mechanically stimulating cells to promote differentiation and physiological effects. [ABSTRACT FROM AUTHOR]

A finite element based method is presented for calculating the acoustic radiation force on arbitrarily shaped elastic and fluid particles. Importantly for future applications, this development will permit the modeling of acoustic forces on complex structures such as biological cells, and the interactions between them and other bodies. The model is based on a non-viscous approximation, allowing the results from an efficient, numerical, linear scattering model to provide the basis for the second-order forces. Simulation times are of the order of a few seconds for an axi-symmetric structure. The model is verified against a range of existing analytical solutions (typical accuracy better than 0.1%), including those for cylinders, elastic spheres that are of significant size compared to the acoustic wavelength, and spheroidal particles. [ABSTRACT FROM AUTHOR]

• 4-AP tethered 1,3,4-oxadiazole derivatives were designed and synthesized. • Compound 9 elicited significant non-competitive type of hAChE inhibition. • Compound 9 showed significant brain permeability in PAMPA-BBB assay. • Compound 9 ameliorated scopolamine- induced cognitive impairment in mice models. • Biochemical analysis using brain homogenates suggested antioxidant activity by 9. The novel hybrids bearing 4-aminopyridine (4-AP) tethered with substituted 1,3,4-oxadiazole nucleus were designed, synthesized, and evaluated for their potential AChE inhibitory property along with significant antioxidant potential. The inhibitory potential (IC 50) of synthesized analogs was evaluated against human cholinesterases (hAChE and hBChE) using Ellman's method. Among all the compounds, 9 with 4-hydroxyl substituent showed maximum hAChE inhibition with the non-competitive type of enzyme inhibition (IC 50 = 1.098 µM; Ki = 0.960 µM). Further, parallel artificial membrane permeation assay (PAMPA-BBB) showed significant BBB permeability in most of the synthesized compounds. Meanwhile, compound 9 also inhibited AChE-induced Aβ aggregation (38.2–65.9%) by thioflavin T assay. The in vivo behavioral studies showed dose-dependent improvement in learning and memory by compound 9. The ex vivo studies also affirmed the significant AChE inhibition and antioxidant potential of compound 9 in brain homogenates. [ABSTRACT FROM AUTHOR]

Six drugs (dapsone, diltiazem, timolol, rosiglitazone, mesalazine, and milnacipran) that were predicted by network-based polypharmacology approaches as potential anti-Alzheimer's drugs, have been subjected in this study for in silico and in vitro evaluation to check their potential against protein fibrillation, which is a causative factor for multiple diseases such as Alzheimer's disease, Parkinson's disease, Huntington disease, cardiac myopathy, type-II diabetes mellitus and many others. Molecular docking and thereafter molecular dynamics (MD) simulations revealed that diltiazem, rosiglitazone, and milnacipran interact with the binding residues such as Asp52, Glu35, Trp62, and Asp101, which lie within the fibrillating region of HEWL. The MM-GBSA analysis revealed -7.86, -5.05, and -10.29 kcal/mol as the binding energy of diltiazem, rosiglitazone, and milnacipran. The RMSD and RMSF calculations revealed significant stabilities of these ligands within the binding pocket of HEWL. While compared with two reported ligands inhibiting HEWL fibrillation, milnacipran depicted almost similar binding potential with one of the known ligands (Ligand binding affinity -10.66 kcal/mol) of HEWL. Furthermore, secondary structure analyses revealed notable inhibition of the secondary structural changes with our candidate ligand; especially regarding retention of the 3/10 α-helix both by DSSP simulation, Circular dichroism, and FESEM-based microscopic image analyses. Taking further into experimental validation, all three ligands inhibited fibrillation in HEWL in simulated conditions as revealed by blue shift in Congo red assay and later expressing percentage inhibition in ThioflavinT assay as well. However, dose-dependent kinetics revealed that the antifibrillatory effects of drugs are more pronounced at low protein concentrations.Communicated by Ramaswamy H. Sarma.