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Elucidating isoniazid resistance using molecular modeling.

Habibah A Wahab¹, Yee-Siew Choong, Pazilah Ibrahim

¹Malaysian Institute of Pharmaceuticals and Nutraceuticals, Ministry of Science, Technology and Innovation, Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia. habibahw@usm.my

Journal of Chemical Information and Modeling

|December 11, 2008

Summary

Isoniazid

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Area of Science:

Biochemistry
Computational Biology
Drug Discovery

Background:

Rising tuberculosis incidence and drug resistance necessitate new drug development.
Isoniazid (INH) is a key anti-tuberculosis drug, but resistance is a growing concern.
Understanding isoniazid resistance mechanisms is crucial for effective treatment.

Purpose of the Study:

To investigate the binding mechanism of isoniazid's active metabolite, isonicotinic acyl-NADH (INADH), to Mycobacterium tuberculosis enoyl-acyl carrier protein reductase (InhA).
To elucidate the molecular basis of isoniazid resistance in mutant InhA strains.
To explore the role of KatG in isoniazid activation and InhA binding.

Main Methods:

Molecular docking simulations to predict binding modes and affinities.

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Molecular dynamics (MD) simulations to analyze protein-ligand interactions and stability.

Free energy calculations to quantify binding strengths and resistance levels.

Main Results:

Isonicotinic acyl-NADH (INADH) exhibits higher binding affinity to wild-type InhA than isoniazid (INH).
Mutant InhA (A94) shows increased mobility, leading to weaker INADH interactions, but only minor resistance.
A water-mediated hydrogen bond is observed in INADH-wild type InhA complex, absent in the mutant complex.

Conclusions:

The conversion of isoniazid to its active form INADH by KatG is essential for binding to InhA.
Structural changes in mutant InhA affect INADH binding, contributing to isoniazid resistance.
Findings provide insights into isoniazid resistance mechanisms and potential drug development strategies.