In silico design of potential drug lead compounds against multidrug–resistant Acinetobacter baumannii Class D carbapenemase OXA-23 and OXA-146 enzyme

Abstract

Multridrug-resistant Acinetobacter baumannii is a serious level threat to public health responsible for at least 12,000 infections a year with at least 500 infections leading to death. A. baumannii has been shown to exhibit extensive resistance against first-line antibiotics as well as carbapenems due to its ability to produce Class D carbapenemases or OXA in the past years. The study aims to design potential drug lead compounds against the OXA-23 and OXA-146 enzymes of A. baumannii in silico. An initial screening of 6,699 compounds from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSPDB) were docked with A. baumannii OXA-23 and OXA-146 was used to identify high affinity binders for ligand design. High-binding affinity compounds were screened with the Lipinski’s Rule of Five and other physicochemical properties. Top binders from the TCMSPDB were cut, combined, and modified to design compounds specific to each enzyme. The compounds considered the most drug-like out of the 400 compounds was R005 (binding energy of -10.8 kcal/mol) for OXA-23 and D005 (binding energy of -9.8 kcal/mol) for OXA-146. These molecules all satisfy the Lipinski’s Rule of Five, the standard measure used for evaluating druglikeness of a compound. Other top designed compounds include R001, R014, R009, and R012 for OXA-23 and D001, D005, D006, D009, and D023 for OXA-146. Molecular dynamics and in vitro and in vivo studies may be performed to determine the aforementioned compounds’ pharmaceutical properties.