Molecular docking and dynamic approach to screen the drug candidate against the Imipenem-resistant CarO porin in Acinetobacter baumannii

Abstract

The multidrug-resistant Acinetobacter baumannii is an emerging nosocomial pathogen in the healthcare sector. Intrinsic resistance in A. baumannii is a significant problem framing a perfect treatment regimen. Also, this organism showed more resistance towards the carbapenem antibiotics, especially for imipenem and meropenem. The development of carbapenem-resistant Acinetobacter baumannii is mainly due to the alteration or loss of the porin region in the outer membrane. The most well-known porin in Acinetobacter baumannii is CarO (carbapenem-associated outer membrane protein). The CarO protein, which functions as a porin channel for carbapenem inflow, may contribute to carbapenem resistance. The current study identifies a potent drug candidate with a better binding affinity to the carbapenem-resistant outer membrane protein. We investigated the specificity of carbapenems such as imipenem, meropenem, ertapenem, biapenem, doripenem, and fluoroquinolone drugs such as sitafloxacin against the imipenem-resistant CarO protein was demonstrated using the computational approaches molecular docking and dynamic simulation for 50 ns. As a result, the high to low enzyme-ligand complex's binding affinity exhibited a greater binding affinity for ertapenem -7.76 kcal·mol^-1 and sitafloxacin -7.75 kcal·mol^-1 than biapenem, doripenem, meropenem, and imipenem. The molecular dynamic simulation and the MMPBSA analysis depicted ertapenem -55.431±25.908 kJ/mol and sitafloxacin -47.154 ± 11.052 kJ/mol with better binding affinity and more stability against the imipenem resistant CarO protein when it compared to other antibiotics.

Keywords: Acinetobacter baumannii; CarO protein; Carbapenem-resistant; MMPBSA analysis; Molecular docking; Molecular dynamic simulation.