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Open AccessFeature PaperArticle

Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

1
Turku Computer Science and Informatics, Department of Future Technologies, University of Turku, FI-20520 Turku, Finland
2
Department of Bioscience and Biotechnology, Institute of KU Biotechnology, Konkuk University, Seoul 05029, South Korea
3
Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Tykistökatu 6A, FI-20520 Turku, Finland
*
Author to whom correspondence should be addressed.
Processes 2019, 7(4), 224; https://doi.org/10.3390/pr7040224
Received: 2 April 2019 / Revised: 15 April 2019 / Accepted: 17 April 2019 / Published: 19 April 2019
(This article belongs to the Special Issue Molecular Dynamics Modeling and Simulation)
Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The selected pharmacophore—NNRRR—yielded a statistically significant 3D-QSAR model containing high confidence scores (R2 = 0.9209, Q2 = 0.8459, and RMSE = 0.3473). The contour maps—comprising hydrogen bond donor, hydrophobic, negative ionic and electron withdrawal effects—from our 3D-QSAR model identified the favorable regions crucial for maximum activity. Furthermore, the external validation of the selected model using enrichment and decoys analysis reveals a high predictive power. Also, the screening capacity of the selected model had scores of 0.94, 0.90, and 8.26 from ROC, AUC, and RIE analysis, respectively. The molecular docking of the highly active compound—C40; 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy) phenyl) sulfamoyl)-1-hydroxy-2-naphthoate—predicted the low-energy conformational pose, and the MD simulation revealed crucial details responsible for the molecular mechanism of binding with Mcl1. View Full-Text
Keywords: Myeloid cell leukemia 1 inhibitors; N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds; molecular dynamics simulations; pharmacophore-based 3D-QSAR model; protein–protein interactions Myeloid cell leukemia 1 inhibitors; N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds; molecular dynamics simulations; pharmacophore-based 3D-QSAR model; protein–protein interactions
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Singaravelu, K.; Balasubramanian, P.K.; Marimuthu, P. Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1. Processes 2019, 7, 224.

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