Unveiling Berberine analogues as potential inhibitors of Escherichia coli FtsZ through machine learning molecular docking and molecular dynamics approach.

The bacterial cell division protein FtsZ, a crucial GTPase, plays a vital role in the formation of the contractile Z-ring, which is essential for bacterial cytokinesis. Consequently, inhibiting FtsZ could prevent the formation of proto-filaments and interfere with the cell division machinery. The remarkable conservation of FtsZ across diverse bacterial species makes it a promising drug target for combating drug resistance. In the present study, 1072 berberine analogues were screened for favorable pharmacokinetic properties. A total of 60 compounds that fulfilled the drug-likeliness criteria and were found to be non-toxic were selected for virtual screening against Escherichia coli FtsZ protein (PDB ID: 8GZY). Molecular docking revealed a strong binding affinity of ZINC000524729297 (- 8.73 kcal/mol) and ZINC000604405393 (and - 8.55 kcal/mol) with FtsZ by strong intermolecular hydrogen bonds and hydrophobic interactions. Subsequently, the docking profiles were validated through a 500 ns MD simulation and MMPBSA analysis of the FtsZ-ligand complexes. The analysis revealed the FtsZ- ZINC524729297 and FtsZ-ZINC000604405393 complexes had the lowest root-mean-square deviation with lowest binding energy and enhanced conformational stability in a dynamic environment. These findings suggest that ZINC524729297 and ZINC000604405393 are the potent lead compound that targets FtsZ and requires further experimental validation.