Abstract
The main study’s purpose is to detect novel natural products (NPs) that are potentially selective MAO-B inhibitors and, additionally, to computationally reposition the marketed drugs with a new therapeutic role for Parkinson’s disease. To reach the goals, 3D similarity search, docking, ADMETox, and drug repurposing approaches were employed. Thus, an unbiased benchmarking dataset was built including selective and nonselective inhibitors for MAO-B compliant with both ligand- and structure-based virtual screening approaches. A retrospective and prospective mining scenario was applied to SPECS NP and DrugBank databases to detect novel scaffolds with potential benefits for Parkinson’s disease patients. Out of the three best selected natural products, cardamomin showed excellently predicted drug-like properties, superior pharmacological profile, and specific interactions with MAO-B active site, indicating a potential selectivity over MAO-B. Two marketed drugs, fenamisal and monobenzone, were proposed as promising candidates repurposed for Parkinson’s disease. The application of shape, physicochemical, and electrostatic similarity searches protocol emerged as a plausible solution to explore MAO-B inhibitors selectivity. This protocol might serve as a rewarding tool in early drug discovery and can be extended to other protein targets.
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Abbreviations
- AUC:
-
Area under the curve
- BMF:
-
Bemis–Murcko framework
- CG4:
-
Chemgauss4
- CS:
-
ComboScore
- CoS:
-
ColorScore
- CoT:
-
ColorTanimoto
- FCoTv:
-
FitColorTversky
- FTv:
-
FitTversky
- FTvC:
-
FitTverskyCombo
- FRED:
-
Flexible ligand–rigid protein docking
- HBA:
-
Hydrogen bond acceptor
- HBD:
-
Hydrogen bond donor
- HRM:
-
Harmine
- LB:
-
Ligand based
- MAO-A:
-
Monoamine oxidase A
- MAO-B:
-
Monoamine oxidase B
- MAOIs:
-
Monoamine oxidase inhibitors
- SPECS NP:
-
SPECS natural products
- O:
-
Overlap
- PDB:
-
Protein Data Bank
- q1 :
-
Query 1
- q2 :
-
Query 2
- RBN:
-
Rotatable bond
- RMSD:
-
Root mean squared deviation
- ROC:
-
Receiver operating characteristic
- ROCS:
-
Rapid overlay of chemical structures
- RCoTv:
-
RefColorTversky
- RTv:
-
RefTversky
- RTvC:
-
RefTverskyCombo
- SB:
-
Structure based
- SAG:
-
Safinamide
- ShT:
-
ShapeTanimoto
- SCo:
-
ScaledColor
- TC:
-
TanimotoCombo
- VS:
-
Virtual screening
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Acknowledgements
The authors thank ChemAxon Ltd. (Marvin Sketch and Instant JChem), OpenEye Ltd., and BIOVIA software Inc. (Discovery Studio Visualizer) for providing academic license, and Dr. Simona Funar-Timofei, “Coriolan Dragulescu” Institute of Chemistry for providing access to STATISTICA software. The authors wish to thank Schrödinger Inc. for providing an academic trial license to complete the calculations for this paper. Project No. 1.2 of the “Coriolan Dragulescu” Institute of Chemistry, Romanian Academy, Timisoara, financially supported the current work.
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Crisan, L., Istrate, D., Bora, A. et al. Virtual screening and drug repurposing experiments to identify potential novel selective MAO-B inhibitors for Parkinson’s disease treatment. Mol Divers 25, 1775–1794 (2021). https://doi.org/10.1007/s11030-020-10155-6
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DOI: https://doi.org/10.1007/s11030-020-10155-6