Identification of Potential Carboxylic Acid-Containing Drug Candidate to Design Novel Competitive NDM Inhibitors: An In-Silico Approach Comprising Combined Virtual Screening and Molecular Dynamics Simulation

Abstract

Metallo-β-lactamases (MBLs) producing bacteria especially the ones with New Delhi metallo-beta-lactamase-1 (NDM-1) and its variants can potentially hydrolyse all the major β-lactam antibiotics, ultimately escalating anti-microbial resistance world-wide. There is a dearth of approved inhibitors to combat NDM and other MBLs producing bacteria. Hence we focussed to find novel inhibitor(s) in-silico which can potentially suppress the activity of NDM/MBLs. A total of 2400 compounds were virtually screened to identify a promising carboxylic acid-containing compound (CID-53986787) analogous to NDM antagonist Captopril. Our lead compound can bind adjacent to the active site zinc ions (Zn1 and Zn2) in all highly resistant NDM variants. CID-53986787 possesses ~ 5–8% higher binding affinity than Captopril, exhibiting molecular interactions with crucial residues that can destabilize the hydrolytic activity of NDM. CID-53986787 was virtually evaluated to ascertain its safe pharmacological/toxicity profile. Molecular dynamics simulation studies further elucidated its stable interaction with the target protein (NDM-1).

Emergence of Meropenem Resistance Among Cefotaxime Non-susceptible Streptococcus pneumoniae: Evidence and Challenges

“…The top-ranked complexes based on the lowest binding energies (highest affinities) were visualized using USCF Chimera (Pettersen et al, 2004) and Discovery Studio (Jejurikar and Rohane, 2021). The intermolecular interactions of the complexes were analyzed to determine the crucial residues of the target that can contribute to the drug binding (Basu et al, 2020;Miryala et al, 2021;Naha et al, 2021;Vasudevan et al, 2021).…”

Datasets comprising the quality validations of simulated protein-ligand complexes and SYBYL docking scores of bioactive natural compounds as inhibitors of Mycobacterium tuberculosis protein-targets

“…The protein structures were placed within the center of the dodecahedron box of uniform edge distance of 1.0 nm, followed by solvation and addition of requisite counter ions (Na + or Cl − ) to the system. Steepest descent algorithm for 50,000 steps and convergence-tolerance of 1000 kJ/mol nm −1 were utilised for energy minimisation following system equilibration under standard NVT (constant Number of particles, Volume and Temperature) and NPT (constant Number of particles, Pressure and Temperature) ensembles for 100 ps [7] , [8] , [9] , [10] , [11] , [12] , [13] , [14] . The trajectories of simulation parameters were visualised using Grace software ( https://plasma-gate.weizmann.ac.il/Grace/ ).…”

Genome sequencing and molecular characterisation of XDR Acinetobacter baumannii reveal complexities in resistance: Novel combination of sulbactam–durlobactam holds promise for therapeutic intervention

“…In NDM, the residues involved in the substrate binding (N220 and D124) were considered as active sites as previously reported. 19 Active-site motifs/residues of all the proteins targets were validated with the CASTp server before performing molecular docking analysis.…”

“…9 Recent studies have demonstrated the potential antibacterial activity of the novel SUL-DUR (βL-βLI) inhibitor combination, which is currently under Phase-III clinical trials and may be helpful in treating infections caused by A. baumannii. 9,11 Our research group has worked extensively to understand the protein-ligand interactions and complex AMR mechanisms of pathogenic bacteria through genomic analyses, [12][13][14][15] in silico structural biology, [16][17][18][19][20] and the systems biology approach. [21][22][23][24] The present study aimed to decipher the efficacy of the SUL-DUR combination against clinical Indian isolates of A. baumannii.…”