For all transformations, the hybrid ligand in protein environment (referred to as "complex") was first energy minimised, followed by a 20 ps NVT equilibration and 2 ns NPT equilibration. Pressure and temperature were maintained at 1 atm and 300 K using a Berendsen barostat (compressibility of 4.57 × 10 -5 bar -1 and relaxation time of 100 fs) and a Langevin thermostat (damping coefficient of 5 ps -1 ), respectively. The production run time was 4 ns. A time step of 2 fs was used. When a hybrid ligand in water environment (referred to as "ligand") was simulated, the entire protocol remained the same except that the NPT equilibration step was only 1 ns long. During both minimisation and equilibration steps, protein backbone atoms were initially constrained to their initial positions and were slowly allowed to relax. Periodic boundary conditions were employed with long-range electrostatics handled by the Particle Mesh Ewald (PME) method. A non-bonded cutoff of 12 Å was used. The van der Waals interactions were smoothly switched off between 10 Å and 12 Å, being linearly decoupled/coupled between λ value 0 and 1 for disappearing and appearing atoms respectively. The standard NAMD soft-core potential was used for the van der Waals terms with the radius-shifiting coefficient of 5 to avoid singularities.