In Silico Evaluation of Potential NDM-1 Inhibitors: An Integrated Docking and Molecular Dynamics Approach

Area of Science:

• * Computational chemistry and structural biology.

Background:

• * Non-fermenting Gram-negative bacteria exhibit high antibiotic resistance, often due to enzymes like New Delhi metallo-beta-lactamase (NDM-1).
• * Developing novel inhibitors against NDM-1 is crucial for combating antimicrobial resistance.

Purpose of the Study:

• * To identify effective small molecule inhibitors against the NDM-1 enzyme using computational approaches.
• * To optimize the discovery process for new lead molecules targeting NDM-1.

Main Methods:

• * Utilized molecular docking with AutoDock4/AutoDock4Zn and molecular dynamics (MD) simulations with GROMACS.
• * Protein and ligand preparation involved UCSF Chimera, AutoDockTools, MarvinSketch, and Avogadro.
• * Assessed binding energy affinities and conformational stability of enzyme-inhibitor complexes.

Main Results:

• * Molecular docking identified M26 and M25 as top candidates with significant binding energy affinities to NDM-1.
• * Molecule M26 demonstrated strong binding, forming six hydrogen bonds with the NDM-1 enzyme.
• * MD simulations confirmed conformational stability and flexibility for NDM-1 complexes with M26, M35, and M37.

Conclusions:

• * Ligands M26, M37, and M35 show considerable potential as lead compounds for novel NDM-1 inhibitors.
• * These identified compounds may offer advantages over existing antibiotics like Meropenem in certain aspects.