5UGS

Crystal structure of M. tuberculosis InhA inhibited by PT501

Summary for 5UGS

• Entry DOI: 10.2210/pdb5ugs/pdb
• Descriptor: Enoyl-[acyl-carrier-protein] reductase [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 5-[(4-cyclopropyl-1,2,3-triazol-1-yl)methyl]-2-(2-methylphenoxy)phenol, ... (6 entities in total)
• Functional Keywords: bacterial enoyl-acp reductase, diphenylether, residence time, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 6
• Total formula weight: 190964.47

Authors

Eltschkner, S.,Pschibul, A.,Spagnuolo, L.A.,Yu, W.,Tonge, P.J.,Kisker, C. (deposition date: 2017-01-10, release date: 2017-02-15, Last modification date: 2024-01-17)

Primary citation

Spagnuolo, L.A.,Eltschkner, S.,Yu, W.,Daryaee, F.,Davoodi, S.,Knudson, S.E.,Allen, E.K.,Merino, J.,Pschibul, A.,Moree, B.,Thivalapill, N.,Truglio, J.J.,Salafsky, J.,Slayden, R.A.,Kisker, C.,Tonge, P.J.
Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.
J. Am. Chem. Soc., 139:3417-3429, 2017

PubMed Abstract: A critical goal of lead compound selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodynamics and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, we predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-containing diphenyl ether with an increased residence time on InhA due to transition-state destabilization rather than ground-state stabilization. In the present work, we evaluate the inhibition of InhA by 14 triazole-based diphenyl ethers and use a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to 3 orders of magnitude. In addition, we identify a novel inhibitor with a residence time on InhA of 220 min, which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.

PubMed: 28151657
DOI: 10.1021/jacs.6b11148

Experimental method

X-RAY DIFFRACTION (2.8 Å)