Stabilization of Microtubules by Taxane Diterpenoids: Insight from Docking and MD simulations

Abstract

Microtubules are formed from the molecules of tubulin, whose dynamics is important for many functions in a cell, the most dramatic of which is mitosis. Taxol is known to interact within a specific site on tubulin and also believed to block cell-cycle progression during mitosis by binding to and stabilizing microtubules. Along with the tremendous potential that taxol has shown as an anticancer drug, clinical problems exist with solubility, toxicity, and development of drug resistance. The crystal structure of taxane diterpenoids, namely, 10, 13-deacetyl-abeo-baccatin-IV (I), 5-acetyl-2-deacetoxydecinnamoyl-taxinine-0.29hydrate (II), 7, 9-dideacetyltaxayuntin (III), and Taxawallin-K (IV), are very similar to the taxol molecule. Considerable attention has been given to such molecules whose archetype is taxol but do not posses long aliphatic chains, to be developed as a substitute for taxol with fewer side effects. In the present work, the molecular docking of these taxane diterpenoids has been carried out with the tubulin alpha-beta dimer (1TUB) and refined microtubule structure (1JFF) using Glide-XP, in order to assess the potential of tubulin binding of these cytotoxic agents. Results show that all the ligands dock into the classical taxol binding site of tubulin. Taxol shows the best binding capabilities. On the basis of docking energy and interactions, apart from taxol, molecule II has a better tendency of binding with 1TUB while molecule I shows better binding capability with bovine tubulin 1JFF. To validate the binding capabilities, molecular dynamics (MD) simulations of the best docked complexes of ligands with 1JFF have been carried out for 15.0 ns using DESMOND. Average RMSD variations and time line study of interactions and contacts indicate that these complexes remain stable during the course of the dynamics. However, taxol and molecule II prevail over other taxoids.

Computational aided mechanistic understanding of Camellia sinensis bioactive compounds against co‐chaperone p23 as potential anticancer agent

“…Three‐dimensional (3D) structure of screened green tea bioactive compounds was collected from the PubChem database (https://pubchem.ncbi.nlm.nih.gov) for re‐docking studies by extra precision (XP) docking mode of GLIDE5.8 module in Schrödinger suite . Briefly, 3D structure of ligands was prepared using LigPrep module in Schrödinger suite while optimized by B3LYP/6‐31G** density functional approach . In addition, various conformations were also generated for the selected ligand and minimized in gas phase via employing optimized potentials for liquid simulations (OPLS) force field .…”

“…Also, p23 protein was processed with PRIME and protein preparation wizards in Schrödinger suite . Herein, protein structures were dissected from co‐crystallized water molecules at the active region to avoid their respective influence on ligand interaction and addition of suitable hydrogen atoms to the carbon atoms was conducted based on their hybridization state followed by structure refinement using protein preparation wizard.…”

“…Also, p23 protein was processed with PRIME and protein preparation wizards in Schrödinger suite. 33 Herein, protein structures were dissected from co-crystallized water molecules at the active region to avoid their respective influence on ligand interaction and addition of suitable hydrogen atoms to the carbon atoms was conducted based on their hybridization state followed by structure refinement using protein preparation wizard. F I G U R E 1 Structure-based virtual screening, molecular interaction profiling, and validation of potential bioactive compounds from the Camellia sinensis as p23 protein inhibitors Correspondingly, distance dependent dielectric constant at 2.0 Å and conjugate gradient algorithm was also applied in subsequent refinement of protein structure at root-mean square deviation of 0.30 Å.…”

Novel anti-tubulin agents from plant and marine origins: insight from a molecular modeling and dynamics study

“…20 PRIME and Protein Preparation wizards of the SCHRODINGER suite have been utilized for the correction and preparation of protein structure as have been reported in our earlier communications. [21][22][23] The b-subunit of the microtubule contains the taxol binding site, which was retained while the other subunit and substrates were deleted. Ligands (molecules 1-12 and taxol) were optimized for their minimum energy congurations.…”

“…Toxicity of the molecules has been predicted using Tox-Tree soware which indicates that taxol is highly toxic whereas other molecules are comparatively less toxic. 23…”