Tubulin-gene Mutation in Drug Resistance in Helminth Parasite: Docking and Molecular Dynamics Simulation Study

Abstract

Drug resistance is an important phenomenon in helminth parasites. Microtubules are among the key chemotherapeutic targets, mutations of which lead to drug resistance. The present study investigated the role of F167Y, E198A, and F200Y mutations in βtubulin protein and their effect on albendazole binding. Brugia malayi β-tubulin protein models were generated using the SwissModel platform by submitting amino acid sequences. Mutations were carried out at amino acid sequences by changing F167Y, E198A, and F200Y. All the model proteins (one wild and three mutated) were docked with the anthelmintic drug albendazole using AutoDock vina-1.1.5. Docking complexes were further investigated for their binding stability by a Molecular Dynamic Simulation study using Gromacs-2023.2. The binding free energies of protein-ligand complexes were analyzed using the MM/PBSA package. The docking study observed decreased ligand binding affinity in F167Y and E198A mutant proteins compared to wild proteins. MD simulation revealed the overall structural stability of the protein complexes during the simulation period. The simulation also observed more stable binding of albendazole in the active pocket of mutant proteins compared to wild-type proteins. Like ligand RMSD, wild-type protein also showed higher amino acid residual flexibility. The flexibility indicates the less compactness of wild β-tubulin protein complexes compared to mutant proteinligand complexes. Van der Waals and electrostatic interactions were found to be the major energy in protein-ligand complexes. However, due to higher solvation energy, wild-type protein showed more flexibility compared to others. The study, therefore, concludes that mutations at positions 167 and 198 of the βtubulin protein contribute to resistance to albendazole through weakened binding affinity. However, the binding of albendazole binding to the proteins leads to structures becoming more stable and compact.