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<p>Parkinson’s disease lacks disease-modifying therapies; MAO-B inhibition remains a symptomatic standard, whereas LRRK2 kinase is a genetically validated Parkinson’s disease target. Here, the resin-acid diterpene sandaracopimaric acid (SCP) was evaluated as a CNS-oriented, hypothesis-generating scaffold rather than as a validated inhibitor. SwissADME predicted high gastrointestinal absorption, blood-brain barrier permeation and non-substrate behavior toward P-gp, with low aqueous solubility as the main developability limitation; ProTox-III suggested low acute oral toxicity (LD<sub>50</sub> approximately 20,000&#xa0;mg·kg⁻¹; class 6). Redocking-validated docking to MAO-B (2V5Z; RMSD = 1.068 Å), LRRK2 (8FO7; RMSD = 1.693 Å), along with a complementary MAO-A selectivity counter-screen (2Z5X; RMSD = 0.270 Å) supported an MAO-B-favouring profile for SCP (-7.9&#xa0;kcal·mol⁻¹) compared with LRRK2 (-6.9&#xa0;kcal·mol⁻¹) and MAO-A (-6.2&#xa0;kcal·mol⁻¹). In 100-ns GROMACS simulations, SCP remained more compactly retained in MAO-B than in LRRK2. MM/GBSA and PCA further supported a more favorable, single-basin MAO-B recognition pattern, whereas LRRK2 displayed a more solvent-exposed and flexible regime. Overall, SCP stands out computationally as an MAO-B-preferring natural scaffold ripe for experimental follow-up, where MAO-A/B enzymatic selectivity testing and LRRK2 kinase assays will serve to validate its true therapeutic viability.</p>

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Sandaracopimaric acid against the MAO-B/LRRK2 axis in Parkinson’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月3日

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  • Oussama Khibech,
  • Amal Elrherabi,
  • Loubna Kharchoufa,
  • Hassan Zrouri,
  • Moneerah J. Alqahtani,
  • Jawaher H. Alqahtani,
  • Joe Miantezila Basilua,
  • Mohamed Bouhrim,
  • Challioui Allal

摘要

Parkinson’s disease lacks disease-modifying therapies; MAO-B inhibition remains a symptomatic standard, whereas LRRK2 kinase is a genetically validated Parkinson’s disease target. Here, the resin-acid diterpene sandaracopimaric acid (SCP) was evaluated as a CNS-oriented, hypothesis-generating scaffold rather than as a validated inhibitor. SwissADME predicted high gastrointestinal absorption, blood-brain barrier permeation and non-substrate behavior toward P-gp, with low aqueous solubility as the main developability limitation; ProTox-III suggested low acute oral toxicity (LD50 approximately 20,000 mg·kg⁻¹; class 6). Redocking-validated docking to MAO-B (2V5Z; RMSD = 1.068 Å), LRRK2 (8FO7; RMSD = 1.693 Å), along with a complementary MAO-A selectivity counter-screen (2Z5X; RMSD = 0.270 Å) supported an MAO-B-favouring profile for SCP (-7.9 kcal·mol⁻¹) compared with LRRK2 (-6.9 kcal·mol⁻¹) and MAO-A (-6.2 kcal·mol⁻¹). In 100-ns GROMACS simulations, SCP remained more compactly retained in MAO-B than in LRRK2. MM/GBSA and PCA further supported a more favorable, single-basin MAO-B recognition pattern, whereas LRRK2 displayed a more solvent-exposed and flexible regime. Overall, SCP stands out computationally as an MAO-B-preferring natural scaffold ripe for experimental follow-up, where MAO-A/B enzymatic selectivity testing and LRRK2 kinase assays will serve to validate its true therapeutic viability.