Evaluation of Docking Machine Learning and Molecular Dynamics Methodologies for DNA-Ligand Systems

Pharmaceuticals

Letícia Cristina Assis¹  Alex Gutterres Taranto¹  Tiago Alves de Oliveira¹  Lucas Rolim Medaglia¹  Eduardo Habib Bechelane Maia²  Alisson Marques da Silva²  Paulo Batista de Carvalho³ 

[1] Department of Bioengineering, Federal University of Sao Joao del-Rei, Praça Dom Helvecio, 74, Fabricas, Sao Joao del-Rei 36301-1601, MG, Brazil;Federal Center for Technological Education of Minas Gerais, Department of Informatics, Management and Design, CEFET MG, Campus Divinopolis, Rua Alvares de Azevedo, 400, Bela Vista, Divinopolis 35503-822, MG, Brazil;Feik School of Pharmacy, University of the Incarnate Word, 4301 Broadway, San Antonio, TX 78209, USA;

关键词: computer drug design;    molecular docking;    molecular dynamic simulation;    virtual screening;    MolAr;    DNA intercalating agents;   

DOI  :  10.3390/ph15020132

来源: DOAJ

【 摘 要 】

DNA is a molecular target for the treatment of several diseases, including cancer, but there are few docking methodologies exploring the interactions between nucleic acids with DNA intercalating agents. Different docking methodologies, such as AutoDock Vina, DOCK 6, and Consensus, implemented into Molecular Architect (MolAr), were evaluated for their ability to analyze those interactions, considering visual inspection, redocking, and ROC curve. Ligands were refined by Parametric Method 7 (PM7), and ligands and decoys were docked into the minor DNA groove (PDB code: 1VZK). As a result, the area under the ROC curve (AUC-ROC) was 0.98, 0.88, and 0.99 for AutoDock Vina, DOCK 6, and Consensus methodologies, respectively. In addition, we proposed a machine learning model to determine the experimental ∆T_m value, which found a 0.84 R² score. Finally, the selected ligands mono imidazole lexitropsin (42), netropsin (45), and N,N′-(1H-pyrrole-2,5-diyldi-4,1-phenylene)dibenzenecarboximidamide (51) were submitted to Molecular Dynamic Simulations (MD) through NAMD software to evaluate their equilibrium binding pose into the groove. In conclusion, the use of MolAr improves the docking results obtained with other methodologies, is a suitable methodology to use in the DNA system and was proven to be a valuable tool to estimate the ∆T_m experimental values of DNA intercalating agents.

【 授权许可】

Unknown