Affiliation:
1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University of Sofia, Sofia, Bulgaria
Abstract
Background:
Tuberculosis is considered a global health problem; hence, the screening and
synthesis of novel tuberculostatic drugs are a necessity. Molecular docking could drastically reduce the
time of hit identification; however, initial validation is required to reduce the false-positive results.
Objective:
Assessment of several searching and scoring algorithms for a custom dataset of hydrazidehydrazone-
based tuberculostatics was conducted to obtain a reliable docking protocol for future virtual
screening.
Methods:
Modification in the scoring functions, size of the grid space, and presence of active waters of a
GOLD 5.3 docking protocol was conducted. Subsequently, side-chain flexibility and ensemble docking
were carried out to assess the role of protein flexibility in the correlation coefficient. In addition, docking
simulations with Glide and free binding energy calculations with MM-GBSA were implemented. The
Pearson correlation coefficient between the experimental and the acquired in silico data was calculated
after each work step. The major interactions between the top-scored ligands and the active site of 2X22
were visualized applying Discovery Studio.
Results:
An optimized GOLD 5.3 docking protocol led to a drastically enhanced Pearson correlation coefficient
of the training set, from 0.461 to 0.823, as well as an excellent pairwise correlation coefficient in
the test set - 0,8405. Interestingly, the Glide docking scores and the free binding energy calculations with
MM-GBSA did not achieve reliable results. During the visualization of the top-ranked compounds, it was
observed that Lys165 played a major role in the formation of stable complexes.
Conclusion:
It could be concluded that the performance of the optimized GOLD 5.3 docking protocol
demonstrated significantly higher reliability against the hydrazide-hydrazone dataset when compared to
Glide docking simulations and MM-GBSA free binding energy calculations. The results could be utilized
for future virtual screenings.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Pharmaceutical Science,Molecular Medicine