Potential colchicine binding site inhibitors unraveled by virtual screening, molecular dynamics and MM/PBSA

Microtubules have been widely studied in recent decades as an important pharmacological target for the treatment of cancer especially due to its key role in the mitosis process. Among the constituents of the microtubules, αβ-tubulin dimers stand out in view of their four distinct interaction sites,...

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Bibliographic Details
Published in:Computers in biology and medicine 2021-10, Vol.137, p.104817, Article 104817
Main Authors: Federico, Leonardo Bruno, Silva, Guilherme Martins, Gomes, Suzane Quintana, Francischini, Isaque Antonio Galindo, Barcelos, Mariana Pegrucci, dos Santos, Cleydson Breno Rodrigues, Costa, Luciano T., Campos Rosa, Joaquín María, de Paula da Silva, Carlos Henrique Tomich
Format: Article
Language:English
Subjects:
Amino acids
Binding Sites
Cell cycle
Chemotherapy
Colchicine
Colchicine binding site
Consensus docking
Dimers
Drug resistance
Free energy
Inhibitors
Libraries
Ligands
Microtubules
Mitosis
MM/PBSA
Modulators
Molecular Docking Simulation
Molecular dynamics
Molecular Dynamics Simulation
Multidrug resistance
Pharmacokinetics
Pipelines
Proteins
Screening
Simulation
Software upgrading
Toxicity
Trajectory analysis
Tubulin
Tubulin modulators
Tubulin Modulators - pharmacology
Virtual screening
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Summary:Microtubules have been widely studied in recent decades as an important pharmacological target for the treatment of cancer especially due to its key role in the mitosis process. Among the constituents of the microtubules, αβ-tubulin dimers stand out in view of their four distinct interaction sites, including the so-called colchicine binding site (CBS) - a promising target for the development of new tubulin modulators. When compared to other tubulin sites, targeting the CBS is advantageous because this site is able to host ligands with lower molecular volume and lipophilicity, thus reducing the chances of entailing the phenomenon of multiple drug resistance (MDR) - one of the main reasons of failure in chemotherapy. However, colchicine, the first ligand ever discovered with affinity towards the CBS, despite modulating the action of microtubules, has shown toxicity in clinical studies. Therefore, in order to expand the known chemical space of scaffolds capable of interacting with CBS and to design non-toxic colchicine binding site inhibitors, we conducted a robust virtual screening pipeline. This has been rigorously validated and consisted of ligand- and structure-based methodologies, which allowed us to select four promising CBS inhibitors called tubLCQF1-4. These four compounds were also evaluated with long trajectories molecular dynamics simulations and respective results were used for the theoretical determination of the free energy released in the formation of the complexes, using the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) methodology. •Development of a rigorous virtual screening pipeline for the development of cancer-fighting inhibitors.•Development of Molecular Dynamics simulations to evaluate the new complexes under study.•Application of the MM/PBSA methodology to determine the binding free energies of complexes formation.•Design of four new promising tubulin colchicine binding site inhibitors.•Expansion and analysis of the chemical and structure diversity of compounds capable of interacting with CBS.
ISSN:0010-4825
1879-0534
DOI:10.1016/j.compbiomed.2021.104817