Virtual screening, optimization and molecular dynamics analyses highlighting a pyrrolo[1,2-a]quinazoline derivative as a potential inhibitor of DNA gyrase B of Mycobacterium tuberculosis

Abstract

Tuberculosis is a disease that remains a significant threat to public health worldwide, and this is mainly due to the selection of strains increasingly resistant to Mycobacterium tuberculosis, its causative agent. One of the validated targets for the development of new antibiotics is DNA gyrase. This enzyme is a type II topoisomerase responsible for regulating DNA topology and, as it is essential in bacteria. Thus, to contribute to the search for new molecules with potential to act as competitive inhibitors at the active site of M. tuberculosis DNA gyrase B, the present work explored a dataset of 20,098 natural products that were filtered using the FAF-Drugs4 server to obtain a total of 5462 structures that were subsequently used in virtual screenings. The consensus score analysis between LeDock and Auto-Dock Vina software showed that ZINC000040309506 (pyrrolo[1,2-a]quinazoline derivative) exhibit the best binding energy with the enzyme. In addition, its subsequent optimization generated the derivative described as PQPNN, which show better binding energy in docking analysis, more stability in molecular dynamics simulations and improved pharmacokinetic and toxicological profiles, compared to the parent compound. Taken together, the pyrrolo[1,2-a]quinazoline derivative described for the first time in the present work shows promising potential to inhibit DNA gyrase B of M. tuberculosis.

Figure 1

Best scored ligands, chemical structure, and analysis of the best-predicted docking pose of PQd calculated by LeDock. (A) Comparison of the binding energies among best scored natural products BS-1 (ZINC000040309506), BS-2 (ZINC000001529323), BS-3 (ZINC000012462127), BS-4 (ZINC000008577218), BS-5 (ZINC000064799791) and, BS-6 (ZINC000065074826), as well as ANP (ZINC000008660410), ATP (ZINC000011524400), and two negative controls NC-1(ZINC000001688375, 2-chloro-5-nitroaniline) and NC-2 (ZINC000003861263, 4-amino-1H-imidazole-5-carboxamide) calculated by LeDock. The ZINC code was omitted from the figure legend only for simplification. (B) Chemical structure of PQd. (C) 3D representation of the 3ZKBL-PQd complex. (D) 2D interaction diagram of the 3ZKBL-PQd complex.

Figure 2

Analysis of the crystallographic pose of ANP. (A) 3D representation of the 3ZKB-ANP complex. (B) 3D representation of 3ZKBL-ANP-complex superimposed with PQd (yellow backbone). (C) 2D interaction diagram of 3ZKBL-ANP complex. (D) Hydrophobic surface representation of 3ZKBL complexed with ANP.

Figure 3

Analysis of the best-predicted docking pose of PQP. (A) 3D representation of 3ZKBL-PQP complex. (B) 2D interaction diagram of 3ZKBL-PQP complex. (C) 3D representation of 3ZKBL-PQP complex superimposed with PQd (yellow backbone). (D) Hydrophobic surface representation of 3ZKBL complexed with PQP.

Figure 4

Comparative poses of co-crystallized ligands of diverse GyrBs and analysis of the best-predicted docking pose of PQPNN. (A) Computationally performed overlay of PQd and co-crystallized ligand-with GyrBs: ADP (cyan), ATP (light green) AX7 (orange), novobiocin (white), ANP (green), PQd (yellow) and PQP (magenta). The black circle highlights the overlapping nitrogen of the co-crystallized ligands. (B) 3D representation of the 3ZKBL-PQPNN complex. (C) 2D interaction diagram of the 3ZKBL-PQPNN complex. (D) 3D representation of PQPNN-3ZKBL complex superimposed with PQd (yellow backbone).

Figure 5

MD analyses of apo-3ZKBL and 3ZKBL complexed to ANP, PQd, and PQPNN. (A) RMSD values. (B) RMSF values. (C) Rg values. All performed with Gromacs.

Figure 6

H-bonds analyses of 3ZKBL complexed with PQd, and PQPNN. (A) H-bonds in complexes. (B) Involvement of ASP79 of the 3ZKBL-PQPNN complex in H-bond formation during MD simulation. (C) Involvement of SER169 of the 3ZKBL-PQPNN complex in H-bond formation during MD simulation. All performed with Gromacs.