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MAO-B plays a key role in Parkinson’s disease by breaking down dopamine, leading to its depletion and contributing to oxidative stress in the brain. Thus, MAO-B inhibition helps preserve dopamine levels, improving motor symptoms and the quality of life for individuals with this neurodegenerative disease. This research aimed to identify known drugs with potential inhibitory activity against MAO-B through computational methods, prospecting their repositioning for Parkinson’s disease treatment. The methodological approach involved a multi-step process, beginning with the search for MAO-B inhibitors in BindingDB using the descriptor “Monoamine Oxidase B Inhibitor” and filtering for compounds with IC50 values up to 1.00 nM. These compounds were then subjected to molecular docking using the GOLD program, with MAO-B crystallographic data from the Protein Data Bank 3PO7, validated through redocking. The pharmacokinetic and toxicological properties of the selected compounds were assessed using QikProp (Schrödinger) and DEREK (Lhasa). In the final stage, drug repositioning was conducted by searching for chemical analogs of the best-performing compounds using the SwissSimilarity webserver. The goal was to identify promising drug candidates with pharmacokinetics suitable for oral administration and central nervous system distribution, as predicted by SwissADME and molecular docking analysis, using rasagiline, safinamide, and selegiline as reference drugs. The first stage of the research identified 3-methyl-8-(4,4,4-trifluorobutoxy)indeno[1,2-c]pyridazin-5-one as a promising candidate for Parkinson’s disease treatment due to its low IC50 (0.0140 nM), favorable predicted pharmacokinetic parameters, and absence of toxicological alerts. Additionally, the similarity-based search using this compound led to the identification of trifluperidol and leflunomide as promising candidates for drug repositioning in Parkinson’s disease treatment. The results obtained align with previous in silico and in vivo studies. Although this study did not identify novel candidates for drug repositioning, its methodology proved effective in screening publicly available chemical spaces for potential therapeutics. This approach may also be valuable for identifying compounds with therapeutic potential for diseases beyond Parkinson’s disease.

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Virtual Screening of Drug Candidates for Repositioning for the Treatment of Parkinson’s Disease

  • 章节

  • 发表日期：

    2025年

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  • Anderson Luiz Pena da Costa,
  • Henrique de Barros Lima,
  • Mariana Pegrucci Barcelos,
  • Carlos Henrique Tomich de Paula da Silva,
  • Gabrieli Santos Oliveira,
  • Carlton Anthony Taft,
  • Lorane Izabel da Silva Hage-Melim

摘要

MAO-B plays a key role in Parkinson’s disease by breaking down dopamine, leading to its depletion and contributing to oxidative stress in the brain. Thus, MAO-B inhibition helps preserve dopamine levels, improving motor symptoms and the quality of life for individuals with this neurodegenerative disease. This research aimed to identify known drugs with potential inhibitory activity against MAO-B through computational methods, prospecting their repositioning for Parkinson’s disease treatment. The methodological approach involved a multi-step process, beginning with the search for MAO-B inhibitors in BindingDB using the descriptor “Monoamine Oxidase B Inhibitor” and filtering for compounds with IC50 values up to 1.00 nM. These compounds were then subjected to molecular docking using the GOLD program, with MAO-B crystallographic data from the Protein Data Bank 3PO7, validated through redocking. The pharmacokinetic and toxicological properties of the selected compounds were assessed using QikProp (Schrödinger) and DEREK (Lhasa). In the final stage, drug repositioning was conducted by searching for chemical analogs of the best-performing compounds using the SwissSimilarity webserver. The goal was to identify promising drug candidates with pharmacokinetics suitable for oral administration and central nervous system distribution, as predicted by SwissADME and molecular docking analysis, using rasagiline, safinamide, and selegiline as reference drugs. The first stage of the research identified 3-methyl-8-(4,4,4-trifluorobutoxy)indeno[1,2-c]pyridazin-5-one as a promising candidate for Parkinson’s disease treatment due to its low IC50 (0.0140 nM), favorable predicted pharmacokinetic parameters, and absence of toxicological alerts. Additionally, the similarity-based search using this compound led to the identification of trifluperidol and leflunomide as promising candidates for drug repositioning in Parkinson’s disease treatment. The results obtained align with previous in silico and in vivo studies. Although this study did not identify novel candidates for drug repositioning, its methodology proved effective in screening publicly available chemical spaces for potential therapeutics. This approach may also be valuable for identifying compounds with therapeutic potential for diseases beyond Parkinson’s disease.