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Virtual screening and drug repurposing experiments to identify potential novel selective MAO-B inhibitors for Parkinson’s disease treatment

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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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Correspondence to Liliana Pacureanu.

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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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