Integrating Atom‐Based 3D‐QSAR, Molecular Docking, and Molecular Dynamics: A Multistep Approach for the Discovery of Potent Adenosine A₂A Receptor Antagonists

ChemistrySelect, Год журнала: 2025, Номер 10(12)

Опубликована: Март 1, 2025

Abstract The rational design of adenosine A 2A receptor antagonists offers a non‐dopaminergic approach to alleviate symptoms Parkinson's disease (PD). Preclinical studies indicate that may inhibit neuronal loss, although human are essential for validating effectiveness. This research focuses on optimizing ligands the through multifaceted method uniting 3D quantitative structure–activity relationship (QSAR) modeling, molecular docking, binding energy calculations, dynamics (MD) simulations, and interaction analysis. robust atom‐based 3D‐QSAR model was developed, achieving predictive performance metrics (R 2 = 0.80, Q 0.65) identifying key structural features associated with bioactivity. Screening 3,958 compounds, five lead molecules (CHEMBL16687, 113142, 1760901, 4289874, 482436) were prioritized based energies (ranging from −12.938 −9.986 kcal/mol). Binding affinity confirmations MMGBSA highlighted significant electrostatic van der Waals interactions. 200 ns MD simulation assessed stability these CHEMBL4289874 showcasing exceptional occupying smallest phase space in principal component analysis (PCA), indicating superior relative other compounds. 2D diagrams elucidated critical ligand‐residue interactions fundamental maintaining integrity. comprehensive investigation positions as an exceptionally promising candidate further development PD treatment.

Язык: Английский

Effect of halogens on 3-[4-(dimethylamino) phenyl]-1-phenylprop-2-en-1-ones: development of a new class of monoamine oxidase-B inhibitors

Applied Biological Chemistry, Год журнала: 2024, Номер 67(1)

Опубликована: Авг. 23, 2024

Abstract Five dimethylamino-based chalcone derivatives (AC) were synthesized and evaluated for their inhibition degree against monoamine oxidase (MAO) enzymes. All AC compounds showed better inhibitory activity MAO-B than that MAO-A. AC4 the highest ability with an IC 50 value of 0.020 µM, similar to a reference drug safinamide (IC = 0.019 µM) MAO-B, followed by AC1 0.068 AC3 0.083 µM). Substituent -F in ring A (AC4) increased inhibition, -H (AC1), -Br (AC3), -Cl (AC2). The selectivity index (SI) was high (SI 82.00) as well other (44.41 98.15). found be reversible inhibitor confirmed through analysis using dialysis method. Interestingly, observed noncompetitive rare case K i values 0.011 ± 0.0036 µM. These experiments is potent selective MAO-B. Molecular docking revealed score (-9.510 kcal/mol). study molecular dynamics modeling protein–ligand complex more stable. It non-cytotoxic L929 cell line. In conclusion, compound shows promise inhibitor.

Язык: Английский

Quantum Insights into Partially Molecular Imprinted Microspheres for Anticancer Therapeutics: Experimental and Theoretical Studies

ACS Biomaterials Science & Engineering, Год журнала: 2024, Номер 10(11), С. 7005 - 7017

Опубликована: Окт. 4, 2024

Drug solubility is a determining factor for controlled release, and solubility-dependent release kinetics can be modified by changing the drug's state in polymer matrix through partial molecular imprinting (PMI), although research this area remains limited. This novel PMI approach creates nanocavities within partially retaining molecule trapping drug. Such method holds promise developing advanced biomaterial-based drug delivery systems anticancer therapies. In study, we developed microspheres designed utilizing to enhance properties. Poly(vinyl alcohol) (PVA) were imprinted with aspirin (ASP) create gemcitabine (GEM) molecules, inducing polymorphic shift of GEM matrix. enhanced properties enabling control over crystallinity rate. The PVA-ASP-GEM complex showed zero-order kinetics, releasing 21.6% 48 h, maintaining steady profile. contrast, nonimprinted PVA-GEM exhibited first-order faster 46.85% same period. Quantum insights from density functional theory (DFT) calculations revealed superior stability complex, binding free energy -56.03 kcal/mol, compared -29.07 kcal/mol PVA-GEM. Molecular dynamics (MD) simulations demonstrated that ASP's presence created restricted GEM's movement, further contributing release. Experimental validation differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), Raman spectroscopy confirmed transitions complex. PMI-based offers promising modulating improving therapeutics, paving way innovative systems.

Язык: Английский