1. Specific interactions between 2-trans enoyl-acyl carrier protein reductase and its ligand: Protein-ligand docking and ab initio fragment molecular orbital calculations.
- Author
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Phusi, Naruedon, Sato, Riku, Ezawa, Takuya, Tomioka, Shogo, Hanwarinroj, Chayanin, Khamsri, Bandit, Kamsri, Pharit, Punkvang, Auradee, Pungpo, Pornpan, and Kurita, Noriyuki
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MOLECULAR orbitals , *CARRIER proteins , *REDUCTASES - Abstract
Abstract 2-trans enoyl-acyl carrier protein reductase (InhA) has been identified as a promising target for the development of novel chemotherapy for tuberculosis. In the present study, a series of heteroaryl benzamide derivatives were selected as potent inhibitors against InhA, and their binding properties with InhA were investigated at atomic and electronic levels by ab initio molecular simulations based on protein-ligand docking, classical molecular mechanics optimizations and ab initio fragment molecular orbital (FMO) calculations. The results evaluated by FMO highlight some key interactions between InhA and the derivatives, indicating that the most potent derivative has strong hydrogen bonds with the Met98 side chain of InhA and strong electrostatic interactions with the nicotinamide adenine dinucleotide cofactor. These findings provide informative structural concepts for designing novel heteroaryl benzamide derivatives with higher binding affinity to InhA. Graphical abstract Interacting structures between the InhA residues and the derivative A4/B4. Red, blue and black lines indicate hydrogen bonding, electrostatic and π-π interactions, respectively. Image 1 Highlights • Interactions between InhA and its inhibitors were studied by molecular simulations. • Ab initio fragment molecular orbital (FMO) method was used for calculations. • The most potent inhibitor has strong hydrogen bonds with Met98 residue of InhA. • The NH group of the inhibitor is important for forming the hydrogen bonds with Met98. • Novel InhA inhibitors with large binding energy were proposed by FMO calculations. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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