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

Letícia Cristina Assis,Lucas Rolim Medaglia,Tiago Alves De Oliveira,Eduardo Habib Bechelane Maia,Paulo Batista De Carvalho,Alex Gutterres Taranto,Alisson Marques Da Silva

doi:10.3390/ph15020132

Abstract

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 ∆Tm 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 ∆Tm experimental values of DNA intercalating agents.

Highlights

Introduction published maps and institutional affilDrugs interacting with DNA are among the most effective anticancer agents [1], but their low selectivity makes them highly toxic, a major drawback that calls for new studies and strategies to develop drugs selective towards DNA in cancerous cells [2].One of the strategies for the development of new drugs is to identify small molecules through a systematic analysis of large groups of compounds with drug-like properties.An experimental approach commonly used is the high throughput screening (HTS), an automated process using robots for a systematic search
A visual inspection was performed on the 1VZK structure to identify the principal forces for molecular recognition
50tons to observe theresignificant were significant mational changeschanges during the trajectory, with the results summarized in Figure 4.inAs can be conformational during the trajectory, with the results summarized observed, ligands 42, and 5142, have with an root-mean-square deviation (RMSD)

Summary

Introduction

Introduction published maps and institutional affilDrugs interacting with DNA are among the most effective anticancer agents [1], but their low selectivity makes them highly toxic, a major drawback that calls for new studies and strategies to develop drugs selective towards DNA in cancerous cells [2].One of the strategies for the development of new drugs is to identify small molecules through a systematic analysis of large groups of compounds with drug-like properties.An experimental approach commonly used is the high throughput screening (HTS), an automated process using robots for a systematic search. Drugs interacting with DNA are among the most effective anticancer agents [1], but their low selectivity makes them highly toxic, a major drawback that calls for new studies and strategies to develop drugs selective towards DNA in cancerous cells [2]. One of the strategies for the development of new drugs is to identify small molecules through a systematic analysis of large groups of compounds with drug-like properties. An experimental approach commonly used is the high throughput screening (HTS), an automated process using robots for a systematic search. An alternative to HTS is the virtual high-throughput screening (vHTS or VS), an in silico method to test large groups of compounds, including databases available online iations It is a costly technique due to the number of compounds to be acquired, the cost of purchase and operation of sophisticated robots [3], and experimental considerations such as stability and solubility of the compounds.

Methods

Results

Discussion

Conclusion