Evaluating the impact of novel hydrazides on various enzyme activities via in vitro and in silico approaches

This study investigates the inhibition of some enzymes. Biochemical processes such as metabolism and neurotransmission rely on enzymes, which are biological catalysts. The abnormal regulation of enzymes, including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase, and α-glucosidase, is linked to conditions such as diabetes and Alzheimer's. There is hope for the treatment of neurodegenerative and metabolic diseases through inhibition of these enzymes. The objective of this work was to investigate the binding processes of these enzymes using molecular docking simulations and to assess the inhibitory effects of thirteen freshly synthesized hydrazide compounds. The chemicals were dissolved in dimethyl sulfoxide (DMSO) and then tested for inhibitory doses (IC₅₀) using enzymatic tests. Protein Data Bank enzyme structures (4EY7, 4BDS, 4W93, and 5NN4) were used in molecular docking experiments to examine interactions inside the active sites. Additionally, SwissADME was used to evaluate pharmacokinetic characteristics. There were noticeable differences in inhibitory potency among the substances that were examined. Compound 12 had the highest binding affinity for AChE, and its considerable inhibitory potential was shown by its IC₅₀ value and MolDock score of -191.597. When it related to BChE, we saw similar patterns; compound 12 had the greatest binding affinity, with a MolDock score of -174.874. Compounds 9 and 12, which had IC₅₀ values of 52.116 µM and 96.270 µM, respectively, showed a significant inhibition of α-amylase and α-glucosidase, indicating that they might be used as therapeutic agents to treat diabetes. Important interactions that stabilize enzyme-ligand complexes were brought to light by molecular docking, such as hydrogen bonding, π-π stacking, π-sulfur contacts, and van der Waals forces. Interactions between π-π and π-sulfur groups produced advantageous stacking configurations with aromatic residues in the enzyme, which was particularly beneficial for compounds containing aromatic rings. As an example, in both AChE and BChE, compound 12 established robust π-sulfur connections with TRP A:86. Furthermore, α-amylase and α-glucosidase showed encouraging binding patterns for compounds 9 and 12, which may be attributed to their unique interactions, including Pi-Sigma and conventional hydrogen bonds, strong aromatic contacts, and minimal steric conflicts. Pharmacokinetic profiling using SwissADME revealed important physicochemical features that impact bioavailability and drug-likeness, including lipophilicity (LIPO), solubility (INSOLU), and saturation (SATU). Optimal ranges were maintained by the majority of compounds; however, structural optimization was necessary for a few molecules that deviated from the norm in terms of lipophilicity and solubility. The promising pharmacokinetic characteristics of compounds 9 and 12 lend credence to their status as promising lead compounds for future research and development. Enzyme inhibitors that showed promise in this investigation may have therapeutic uses in the treatment of metabolic and neurological disorders. In order to optimize molecules for therapeutic development, the results highlight the significance of structure-based design. To make these compounds more suitable for clinical usage, more experimental validation is needed. The goal should be to improve their selectivity and potency by modifying them chemically in a way that changes hydrogen bonding and hydrophobic interactions.