Computational Modelling and Profiling of Torsional Angles. The dynamics of the torsional angles of methylated AC ring analogs 4-6 were studied computationally by carrying out a relaxed coordination scan with Schrödinger Suite's Jaguar software. In these studies, an optimized geometry was generated, and dihedral angle c was varied in an iterative nature by 10° (Scheme 1A). A full 360° beyond the first coplanar orientation was scanned in order to establish a full and iterative 0-360° window (Scheme 1B). Of note, the three methoxy groups on the A ring did not reorganize during the simulations due to their proximity, and this caused enantiomers with different energies near the ground-states. Thus, for ground-state profiling, the lowest energy of each enantiomer was chosen to as the most accurate ground-state for each pose, and these values are plotted from 0-180° in Scheme 1C. Scheme 1. Dihedral Angle Modeling of 3-6. (A) Illustration of torsional angle of interest, along with table describing key data points from computational optimization and torsional scan studies (M06-2X-D3/6-311G**). (B) 360° torsional profile of 3-6 for approximating chiral axis stability. 30 kcal/mol is viewed as a threshold for the rotational barrier about a chiral axis above which molecules can be developed as single enantiomers. (C) Ground-state dihedral profiling of 3-6, along with known tubulin-bound (-)-colchicine dihedral angle (pdb 1SAO). The dihedral angle of the minimized structures for MTC (3) was 129.1°, although profiling of its dihedral angle revealed an energetically comparable pose at ~50° (blue, Scheme 1C). This observation, as well as local energetic maxima at its planar and perpendicular orientations, have been observed previously. A similar set of two near energetically equivalent local minimum were also observed for MB-MTC (5) at ~120° and 60°, shifting towards the perpendicular orientation (magenta, Scheme 1C). These two energetic minima could be considered to be in a 'colchicine-type' pose (~ 60°), representing the approximate dihedral angle of the AC ring in colchicine, and 'isocolchicine-type' pose (~120°), which is the dihedral angle found in the AC ring in isocolchicine (see Scheme 1A