Exploring natural products as multi-target-directed drugs for Parkinson's disease: an in-silico approach integrating QSAR, pharmacophore modeling, and molecular dynamics simulations.

Parkinson's disease is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the midbrain. Current treatments provide limited symptomatic relief without halting disease progression. A multi-targeting approach has shown potential benefits in treating neurodegenerative diseases. In this study, we employed in silico approaches to explore the COCONUT natural products database and identify novel drug candidates with multi-target potential against relevant Parkinson's disease targets. QSAR models were developed to screen for potential bioactive molecules, followed by a hybrid virtual screening approach involving pharmacophore modeling and molecular docking against MAO-B, AA2AR, and NMDAR. ADME evaluation was performed to assess drug-like properties. Our findings revealed 22 candidates that exhibited the desired pharmacophoric features. Particularly, two compounds: CNP0121426 and CNP0242698 exhibited remarkable binding affinities, with energies lower than -10 kcal/mol and promising interaction profiles with the chosen targets. Furthermore, all the ligands displayed desirable pharmacokinetic properties for brain-targeted drugs. Lastly, molecular dynamics simulations were conducted on the lead candidates, belonging to the dihydrochalcone and curcuminoid class, to evaluate their stability over a 100 ns timeframe and compare their dynamics with reference complexes. Our findings revealed the curcuminoid CNP0242698 to have an overall better stability with the three targets compared to the dihydrochalcone, despite the high ligand RMSD, the curcuminoid CNP0242698 showed better protein stability, implying ligand exploration of different orientations. Similarly, AA2AR exhibited higher stability with CNP0242698 compared to the reference complex, despite the high initial ligand RMSD due to the bulkier active site. In NMDAR, CNP0242698 displayed good stability and less fluctuations implying a more restricted conformation within the smaller active site of NMDAR. These results may serve as lead compounds for the development and optimization of natural products as multi-target disease-modifying natural remedies for Parkinson's disease patients. However, experimental assays remain necessary to validate these findings.Communicated by Ramaswamy H. Sarma.

Identification of hot spot residues on serine-arginine protein kinase-1 by molecular dynamics simulation studies.

Serine-arginine protein kinase-1 (SRPK1) is a highly specific kinase that recognizes serine-arginine dipeptide repeats and phosphorylates SR rich splicing factor ASF/SF2 in a cell-cycle regulated manner. SRPK1 processively phosphorylates serine residues on its substrate ASF/SF2. Elevated expression pattern of both SRPK1 and ASF/SF2 and their association with various carcinomas have established SRPK1 as a potent target for drug design against cancers. In order to develop specific inhibitors the binding of ASF/SF2 to SRPK1 is desired to be selectively interrupted. We have performed molecular dynamics simulation studies on crystal structure of SRPK1 complex with ASF/SF2. The ASF/SF2 acquired a stable binding on the surface of SRPK1 with strong attractive forces. Analysis revealed that there was no major position shifting of the core ß-sheet region within the catalytic site of SRPK1 when present in the state of ASF/SF2 bound in comparison to apo form. Global motions of SRPK1 indicated that major stable structural changes occurred after the substrate binding. The interactions between SRPK1 and ASF/SF2 were examined and calculated during molecular dynamics simulation of 1 µs. Molecular dynamics study indicated Arg84, Lys85, Leu86, Lys174, Tyr227 and Leu479 residues of SRPK1 as essential hot spots involved in the stable binding with substrate. Structural analysis of the binding affinity and hot spot investigation provided significant information on ASF/SF2 binding which may also be considered for designing of the novel specific inhibitors of SRPK1 for the applications in cancer therapy.Communicated by Ramaswamy H. Sarma.

Structural studies on dihydrouridine synthase A (DusA) from Pseudomonas aeruginosa.

Dihydrouridination is one of the abundant modifications in tRNA editing. The presence of dihydrouridine is attributed to tRNA stability desired for the efficient gene translation process. The conversion of uridine to dihydrouridine is catalyzed by flavine containing enzyme called dihydrouridine synthase (Dus). We report first ever information about DusA enzyme from Pseudomonas aeruginosa in form of structural and functional studies. The gene coding for DusA from P. aeruginosa (PADusA) was cloned, expressed and purified, using recombinant DNA technology methods. Thermal and chemical stability of PADusA was determined with respect to temperature and urea-induced equilibrium unfolding experiments, with monitoring the change of ellipticity at 200-260 nm by Circular Dichroism (CD) spectroscopy. Unfolding studies revealed that PADusA has acquired a stable tertiary structure fold with a Tm value of 46.2 °C and Cm of 2.7 M for urea. The enzyme contains 43% α-helices and 16% ß-strands. The three dimensional structure of PADusA was modeled using insilico methods. In order to understand the mechanism of substrate recognition and catalysis, tRNA and puromycin were docked on PADusA structure and their binding was analyzed. The structural features suggested that PADusA may also form a novel target for structure based drug design of antimicrobial agents.