Design of inhibitors to Klebsiella pneumoniae aspartate semialdehyde dehydrogenase towards hospital-acquired infections.

Hospital-acquired infections (HAIs) caused by viral, bacterial, and fungal pathogens have resulted in numerous deaths all over the world. Klebsiella pneumoniae (Kp) is a drug-resistant Gram-negative bacterium responsible for HAIs. Aspartate β-semialdehyde dehydrogenase (ASADH) enzyme is crucial for the survival of Kp since it is involved in the biosynthetic pathway responsible for the production of essential amino acids and important metabolites. This pathway is absent in mammals and hence design of inhibitors for Kp ASADH becomes a good strategy for the treatment of HAIs. In this study, computational methodologies were employed to design inhibitors targeting Kp ASADH. Key active site residues were identified through the analysis of binding interactions with two established lead compounds, 4-nitro-2-phosphonobenzoic acid and (S)-methyl cysteine sulfoxide. A virtual screening of compounds from the NCI Diversity Database was conducted using molecular docking within the active site in the presence of coenzyme NADPH. Drug-like properties of the identified hit compounds were subsequently evaluated. These molecules were further validated using molecular dynamics simulations to assess their structural stability. The finalized hit compounds underwent additional stability assessments through normal mode analysis, mechanical stiffness evaluation, principal component analysis, and binding energy calculations using MM/GBSA. ADMET profiles of the final compounds were examined.