Journal
PHARMACEUTICALS
Volume 15, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/ph15020132
Keywords
computer drug design; molecular docking; molecular dynamic simulation; virtual screening; MolAr; DNA intercalating agents
Categories
Funding
- Research Support Foundation of the State of Minas Gerais-FAPEMIG-Brazil [CDS-APQ-02742-17, APQ-00855-19, APQ-01733-21]
- National Council for Scientific and Technological Development-CNPq-Brazil [305117/2017-3, 426261/2018-6, 310108/2020-9]
- PPBE
- PPGCF/UFSJ
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This study evaluated different docking methodologies to analyze the interactions between nucleic acids and DNA intercalating agents. A machine learning model was used to estimate the experimental Delta T-m value. The results showed that MolAr is an effective docking method and can be used to estimate the experimental values of DNA intercalating agents.
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 Delta 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 Delta T-m experimental values of DNA intercalating agents.
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