Computational Evaluation of Potential c-Abl Kinase Inhibitors for Parkinson's Disease: QSAR, Docking, Bioisosteric
Amal Kadimi1, Haruna Isiyaku Umar2,3,4, Neeraj Kumar5
1Laboratory of Biotechnology and Natural Resources Valorization, Faculty of Sciences, Ibn Zohr University, 80060, Agadir, Morocco.
Abstract:
Inhibiting c-Abl kinase pharmacologically is necessary because of its role in oxidative stress and neurodegeneration. When activated, it causes the accumulation of α-synuclein and dopaminergic neuron damage, leading to Parkinson's disease (PD). Reports of the effectiveness of c-Abl inhibitors repurposed for PD were accompanied by both hope and numerous concerns. Therefore, there is an urgent need for alternative c-Abl inhibitors. We employed a machine-learning-based QSAR model to identify potential actives against c-Abl kinase, screening selected FDA-approved and phase 1 drugs; optimizing the compounds' structures through bioisostere replacement; conducting molecular docking algorithms (HTVS, SP, XP, and Prime's Molecular Mechanics with Generalized Born and Surface Area (Prime-MMPBSA)); in silico pharmacokinetic profiling; and structural stability and dynamics studies for 200 ns. From 3605 drugs and 1456 bioisosteres, two bioisosteres of indobufen (indobufen 25 and 22) showed promising potential against c-Abl kinase. As the two bioisosteres returned the closest docking scores (14.880 and - 14.265 kcal mol-1, respectively) to the control drug (nilotinib, - 15.312 kcal mol-1), the Prime-MMGBSA calculations returned - 81.92 and - 84.07 kcal mol-1, respectively; MMPBSA calculations after a 200-ns MD simulation run returned - 48.20 ± 3.69 kcal mol-1 and - 49.94 ± 3.05 kcal mol-1, respectively. This indicates their stability compared to other test compounds, as supported by the RMSD, RMSF, PCA, and DCCM results. Finally, both bioisosteres interacted with MET 318, ASP 381, TYR 253, ALA 269, and PHE 317 in the c-Abl active site. We present these bioisosteres as potential candidates for the treatment or management of PD targeting c-Abl kinase. However, in vitro and in vivo experiments to validate the findings are urgently required.
Insights
New drug candidates targeting c-Abl kinase show promise for Parkinson's disease (PD) treatment. Computational methods identified two indobufen bioisosteres with potential therapeutic benefits for PD by inhibiting c-Abl kinase activity.
Area of Science:
- Neuroscience
- Pharmacology
- Computational Chemistry
Background:
- c-Abl kinase plays a crucial role in oxidative stress and neurodegeneration, implicated in Parkinson's disease (PD) pathogenesis.
- Activated c-Abl kinase leads to α-synuclein accumulation and dopaminergic neuron damage, characteristic of PD.
- Existing c-Abl inhibitors repurposed for PD show promise but raise concerns, necessitating novel therapeutic strategies.
Purpose of the Study:
- To identify novel c-Abl kinase inhibitors for potential Parkinson's disease (PD) treatment using computational approaches.
- To optimize potential drug candidates through bioisostere replacement and evaluate their efficacy and stability.
Main Methods:
- Employed a machine-learning-based Quantitative Structure-Activity Relationship (QSAR) model to screen FDA-approved and Phase 1 drugs.
- Utilized molecular docking algorithms (HTVS, SP, XP, Prime-MMPBSA) and in silico pharmacokinetic profiling.
- Conducted 200 ns molecular dynamics (MD) simulations to assess structural stability and binding interactions.
Main Results:
- Screened 3605 drugs and 1456 bioisosteres, identifying two indobufen bioisosteres (indobufen 25 and 22) with high potential against c-Abl kinase.
- These bioisosteres exhibited docking scores comparable to the control drug nilotinib and favorable binding free energies.
- MD simulations confirmed the stability of the identified bioisosteres, showing specific interactions within the c-Abl active site.
Conclusions:
- Two indobufen bioisosteres demonstrate significant potential as therapeutic agents for Parkinson's disease (PD) by targeting c-Abl kinase.
- The identified compounds are stable and exhibit favorable binding characteristics, suggesting their suitability for further investigation.
- In vitro and in vivo validation studies are essential to confirm the therapeutic efficacy of these novel c-Abl kinase inhibitors for PD.
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