Developing multifaceted drug synergistic therapeutic strategy against neurological disorders

Izza Irum; Fariha Khan; Muhammad Sufyan; Syeda Hafiza Benish Ali; Sidra Rehman

doi:10.1016/j.compbiomed.2024.109495

Developing multifaceted drug synergistic therapeutic strategy against neurological disorders

Comput Biol Med. 2024 Dec 17:185:109495. doi: 10.1016/j.compbiomed.2024.109495. Online ahead of print.

Authors

Izza Irum¹, Fariha Khan¹, Muhammad Sufyan², Syeda Hafiza Benish Ali¹, Sidra Rehman³

Affiliations

¹ Department of Biosciences, COMSATS University Islamabad (CUI), Park Road, Islamabad, 45550, Pakistan.
² Department of Bioinformatics and Biotechnology, Government College University Faisalabad, Faisalabad, 38000, Pakistan.
³ Department of Biosciences, COMSATS University Islamabad (CUI), Park Road, Islamabad, 45550, Pakistan. Electronic address: sidrarehman@comsats.edu.pk.

PMID: 39693689
DOI: 10.1016/j.compbiomed.2024.109495

Abstract

Drug synergism can alter the ultimate biological effects and bioavailability of phytoconstituents. Acetylcholinesterase (AChE) inhibitors as symptomatic drugs are potent therapeutic regimen for neurodegenerative diseases. In this context, this study characterized the synergistic antioxidant, anti-inflammatory and anti-AChE effects of the selected phytochemicals including standard drugs followed by enzyme kinetics, structure-based ligands screening and molecular dynamics simulation study. The synergistic interactions were evaluated through Isoradiation and Synergy finder 3.0 methods. The combinations of Quercetin (QCT), Folic acid (FA), and Swertiamarin (SWT) with specific reference drugs were studied. The combinations of SWT + GA (Gallic acid) and FA + GA at 1:1 (γ:0.10 & 0.08, respectively) showed the significant synergistic antioxidant effect via ABTS assay. Further, in combination, QCT + SWT showed the maximum synergistic effect (γ: 0.02-0.13) in anti-inflammatory assay. Moreover, the combinations QCT, FA, and SWT with reference drug, Donepezil (DP), illustrated potent synergistic activity as anti-AChE in 1:1 proportion (γ: 0.18). The interaction pattern of phytochemicals significantly exhibited synergism (γ < 1) depicting their optimum activity in combinations compared to individual components. Enzyme kinetics evaluation showed the competitive binding of SWT with AChE as of donepezil. All the parameters of ADMET study proposed the QCT and SWT as acceptable oral drug molecules. Computational docking study revealed that QCT and SWT with lowest RMSD (1.096, 2.104) and lowest docking score (-9.831, -7.435 kcal/mol) showed maximum binding efficacy. Furthermore, molecular simulation study depicted the stability of protein-ligand complexes. These findings provide novel insight in the development of dietary treatment based on their synergistic effects for neurological disorders as optimum alternative therapeutic agents.

Keywords: Alzheimer's disease; Anti-acetylcholinesterase activity; Anti-inflammatory activity; Antioxidant activity; Enzyme kinetics; Molecular docking; Molecular dynamics simulations; Phytochemicals synergism; Quercetin; Swertiamarin.