Fig 1.
Schematic diagram of the utilized in-silico approaches in the virtual screening strategy of BTZ analogs.
Fig 2.
(a) Superimposition illustration of the predicted docking pose (in pink) and the native binding mode of PBTZ169 (in dark cyan), (b) 3D and (c) 2D molecular interactions of the expected docking pose of PBTZ169 complexed with DprE1 enzyme.
Fig 3.
(a) Predicted covalent docking scores and (b) estimated binding energy of test Set II inhibitors complexed with DprE1 enzyme relative to the comparable to the experimental binding energy (ΔGexp).
Table 1.
Predicted covalent docking scores (in kcal/mol) and binding features of PBTZ169 and the most potent BTZ analogs within the DprE1 active sitea.
Fig 4.
3D and 2D representations of (a) PubChem-155-924-621, (b) PubChem-127-032-794, and (c) PubChem-155-923-972 complexed with DprE1 enzyme.
Fig 5.
Calculated binding energies of PubChem-155-924-621, PubChem-127-032-794, PubChem-155-923-972, and PBTZ169 complexed with DprE1 enzyme over 1, 10, 25, and 100 ns MD simulations.
Fig 6.
Binding energy decomposition for PubChem-155-924-621, PubChem-127-032-794, PubChem-155-923-972, and PBTZ169 complexed with DprE1 enzyme throughout 100 ns MD simulations.
Fig 7.
(a) The energy contribution of the most significant residues to the overall binding energy and (b) 2D molecular interactions of binding modes of (i) PubChem-155-924-621, (ii) PubChem-127-032-794, (iii) PubChem-155-923-972, and (iv) PBTZ169 complexed with DprE1 enzyme according to the final snapshot throughout a 100 ns MD simulation.
Fig 8.
(a) Estimated binding energy per trajectory, (b) CoM distances, and (c) RMSD of the backbone atoms from the initial conformational of PubChem-155-924-621 (in dark cyan), PubChem-127-032-794 (in blue), PubChem-155-923-972 (in violet), and PBTZ169 (in black) towards DprE1 enzyme during the 100 ns MD course.
Fig 9.
Estimated (a) RMSF, (b) Rg, and (c) SASA for apo- (in grey), PubChem-155-924-621- (in dark cyan), PubChem-127-032-794- (in blue), PubChem-155-923-972- (in violet), and PBTZ169-DprE1 (in black) over 100 ns MD simulations.
Fig 10.
Number of H-bonds for PubChem-155-924-621, PubChem-127-032-794, PubChem-155-923-972, and PBTZ169 complexed with DprE1 enzyme during the 100 ns MD simulations.
Fig 11.
Estimated physiochemical features of PubChem-155-924-621, PubChem-127-032-794, PubChem-155-923-972, and PBTZ169 as DprE1 inhibitors.
Table 2.
Pharmacokinetic and toxicity profile for the identified BTZ analogs and PBTZ169.