Identification of potential inhibitors against <i>Escherichia coli</i> Mur D enzyme to combat rising drug resistance: an <i>in-silico</i> approach
Creators: name: Gaur, Vinita
name: Kumar, Neeraj
name: Vyas, Ashish
name: Chowdhury, Debabrata
name: Singh, Joginder
name: Bera, Surojit
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Space Science
subject: Medicine
subject: Microbiology
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Immunology
subject: FOS: Clinical medicine
subject: Biological Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Infectious Diseases
subject: FOS: Health sciences

description: Indiscriminate use of anti-microbial agents has resulted in the inception, frequency, and spread of antibiotic resistance among targeted bacterial pathogens and the commensal flora. Mur enzymes, playing a crucial role in cell-wall synthesis, are one of the most appropriate targets for developing novel inhibitors against antibiotic-resistant bacterial pathogens. In the present study, <i>in-silico</i> high-throughput virtual (HTVS) and Standard-Precision (SP) screening was carried out with 0.3 million compounds from several small-molecule libraries against the <i>E. coli</i> Mur D enzyme (PDB ID 2UUP). The docked complexes were further subjected to extra-precision (XP) docking calculations, and highest Glide-score compound was further subjected to molecular simulation studies. The top six virtual hits (S1–S6) displayed a glide score (G-score) within the range of −9.013 to −7.126 kcal/mol and compound S1 was found to have the highest stable interactions with the Mur D enzyme (2UUP) of E. <i>coli</i>. The stability of compound S1 with the Mur D (2UUP) complex was validated by a 100-ns molecular dynamics simulation. Binding free energy calculation by the MM-GBSA strategy of the S1-2UUP (Mur D) complex established van der Waals, hydrogen bonding, lipophilic, and Coulomb energy terms as significant favorable contributors for ligand binding. The final lead molecules were subjected to ADMET predictions to study their pharmacokinetic properties and displayed promising results, except for certain modifications required to improve QPlogHERG values. So, the compounds screened against the Mur D enzyme can be further studied as preparatory points for <i>in-vivo</i> studies to develop potential drugs. HIGHLIGHTS<i>E.coli</i> is a common cause of urinary tract infections.<i>E.coli</i> MurD enzyme is a suitable target for drug development.Novel inhibitors against <i>E.coli</i> MurD enzyme were identified.Molecular dynamics studies identified <i>in-silico</i> potential of identified compound.ADMET predictions and Lipinski’s rule of five studies showed promising results. <i>E.coli</i> is a common cause of urinary tract infections. <i>E.coli</i> MurD enzyme is a suitable target for drug development. Novel inhibitors against <i>E.coli</i> MurD enzyme were identified. Molecular dynamics studies identified <i>in-silico</i> potential of identified compound. ADMET predictions and Lipinski’s rule of five studies showed promising results.