Exploration of potential hit compounds targeting 1-deoxy-d-xylulose 5-phosphate reductoisomerase (IspC) from Acinetobacter baumannii: an in silico investigation

• Published in: 3 Biotech Vol. 14; no. 3; p. 72
• Main Authors: Zia, Mahrukh Parveez, Jain, Monika, Muthukumaran, Jayaraman, Singh, Amit Kumar
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.03.2024; Springer Nature B.V
• Subjects: Acinetobacter baumannii; Agriculture; Antibiotics; Binding sites; biochemical pathways; Bioinformatics; Biomaterials; Biotechnology; Cancer Research; Carbapenems; Chemistry; Chemistry and Materials Science; computer simulation; D-Xylulose 5-phosphate; enamines; enzymes; Free energy; Gibbs free energy; Ligands; Molecular dynamics; Original; Original Article; pathogens; Reductoisomerase; species; Stem Cells; Structural stability; Substrate inhibition; surface area; Xylulose; MD simulations; MEP pathway; High-throughput virtual screening; DXR; IspC; Acinetobacter baumannii
• ISSN: 2190-572X; 2190-5738
• DOI: 10.1007/s13205-024-03923-w

The emergence of carbapenem-resistant Acinetobacter baumannii , a highly concerning bacterial species designated as a Priority 1: Critical pathogen by the WHO, has become a formidable global threat. In this study, we utilised computational methods to explore the potent molecules capable of inhibiting the IspC enzyme, which plays a crucial role in the methylerythritol 4-phosphate (MEP) biosynthetic pathway. Employing high-throughput virtual screening of small molecules from the Enamine library, we focused on the highly conserved substrate binding site of the DXR target protein, resulting in the identification of 1000 potential compounds. Among these compounds, we selected the top two candidates (Z2615855584 and Z2206320703) based on Lipinski’s rule of Five and ADMET filters, along with FR900098, a known IspC inhibitor, and DXP, the substrate of IspC, for molecular dynamics (MD) simulations. The MD simulation trajectories revealed remarkable structural and thermodynamic stability, as well as strong binding affinity, for all the IspC-ligand complexes. Furthermore, binding free energy calculations based on MM/PBSA (Molecular Mechanics/Poisson–Boltzmann Surface Area) methodology demonstrated significant interactions between the selected ligand molecules and IspC. Taking into consideration all the aforementioned criteria, we suggest Z2206320703 as the potent lead candidate against IspC.