Abstract
An important kinetic parameter for drug efficacy is the residence time of a compound at a drug target, which is related to the dissociation rate constant koff. For the essential antimycobacterial target InhA, this parameter is most likely governed by the ordering of the flexible substrate binding loop (SBL). Whereas the diphenyl ether inhibitors 6PP and triclosan (TCL) do not show loop ordering and thus, no slow-binding inhibition and high koff values, the slightly modified PT70 leads to an ordered loop and a residence time of 24 minutes. To assess the structural differences of the complexes from a dynamic point of view, molecular dynamics (MD) simulations with a total sampling time of 3.0 µs were performed for three ligand-bound and two ligand-free (perturbed) InhA systems. The individual simulations show comparable conformational features with respect to both the binding pocket and the SBL, allowing to define five recurring conformational families. Based on their different occurrence frequencies in the simulated systems, the conformational preferences could be linked to structural differences of the respective ligands to reveal important determinants of residence time. The most abundant conformation besides the stable EI* state is characterized by a shift of Ile202 and Val203 toward the hydrophobic pocket of InhA. The analyses revealed potential directions for avoiding this conformational change and, thus, hindering rapid dissociation: (1) an anchor group in 2'-position of the B-ring for scaffold stabilization, (2) proper occupation of the hydrophobic pocket, and (3) the introduction of a barricade substituent in 5'-position of the diphenyl ether B-ring.
Highlights
The death rate has dropped by 45% over the past two decades, tuberculosis (TB) is still a globally present disease
InhA-inhibitors target the fatty acid synthesis II (FASII) of mycobacteria by disabling the hydrogenation of the unsaturated precursors of the long and hydrophobic mycolic acids, which are necessary for proper construction of the largely impermeable Mycobacterium tuberculosis (Mtb) cell wall [4]
This study is based on three major hypotheses: (1) The ternary complex of PT70 with InhA and NAD+ represents the EIÃ state of the system
Summary
The death rate has dropped by 45% over the past two decades, tuberculosis (TB) is still a globally present disease. Molecular Determinants of Residence Time of InhA Inhibitors of isoniazid, rifampicin, pyrazinamide, and ethambutol for a period of six months—has cured over 56 million people since 1995, but the emergence of multi- and extensively drug-resistant strains of Mycobacterium tuberculosis (MDR-TB and XDR-TB) demands new, high-affinity inhibitor classes, which are unaffected by mycobacterial resistances [1,2,3]. Diphenyl ethers are one class of inhibitors currently under investigation. They bind directly to the well validated mycobacterial drug target enoyl-ACP reductase (InhA) without the necessity for prior activation by the enzyme catalase-peroxidase (KatG) [3]. InhA-inhibitors target the fatty acid synthesis II (FASII) of mycobacteria by disabling the hydrogenation of the unsaturated precursors of the long and hydrophobic mycolic acids, which are necessary for proper construction of the largely impermeable Mycobacterium tuberculosis (Mtb) cell wall [4]
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