In silico Analysis of Novel Mutation ala102pro Targeting pncA Gene of M. Tuberculosis

Lakshmipathy, Dhanurekha; Gayathri, R; Therese, Lily; Vetrivel, Umashankar; Sivashanmugam, Muthukumaran; Rajendiran, Sunitha; Ramaswamy, Sridhar; Hn, Madhavan; Meenakshi, N.

doi:10.4172/jcsb.1000103

Cited by 2 publications

(4 citation statements)

References 16 publications

(22 reference statements)

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“…Maximum 32 conformers were considered for PZA. A grid was generated using Schrodinger's Receptor grid generation application around the active site residues Cys138, Thr135, Ala134, Ile133, Lys96, His71, Trp68, Phe58, His57, His51, Asp49, Phe13, and Asp8 …”

Section: Methodsmentioning

confidence: 99%

“…A grid was generated using Schrodinger's Receptor grid generation application around the active site residues Cys138, Thr135, Ala134, Ile133, Lys96, His71, Trp68, Phe58, His57, His51, Asp49, Phe13, and Asp8. 55,56 Extra precision docking protocol 57 was implemented. Total ligand-receptor interaction energy was calculated on the basis of van der Waals interaction forces, electrostatic energy and H-bond interactions within the ligand and receptor.…”

Section: Receptor-ligand Interactionmentioning

confidence: 99%

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Role of pncA gene mutations W68R and W68G in pyrazinamide resistance

Aggarwal

Singh

Grover

et al. 2017

J of Cellular Biochemistry

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Mycobacterium tuberculosis (Mtb) resistance toward anti-tuberculosis drugs is a widespread problem. Pyrazinamide (PZA) is a first line antitubercular drug that kills semi-dormant bacilli when converted into its activated form, that is, pyrazinoic acid (POA) by Pyrazinamidase (PZase) enzyme coded by pncA gene. In this study, we conducted several analyses on native and mutant structures (W68R, W68G) of PZase before and after docking with the PZA drug to explore the molecular mechanism behind PZA resistance caused due to pncA mutations. Structural changes caused by mutations were studied with respect to their effects on functionality of protein. Docking was performed to analyze the protein-drug binding and comparative analysis was done to observe how the mutations affect drug binding affinity and binding site on protein. Native PZase protein was observed to have the maximum binding affinity in terms of docking score as well as shape complementarity in comparison to the mutant forms. Molecular dynamics simulation analyses showed that mutation in the 68th residue of protein results in a structural change at its active site which further affects the biological function of protein, that is, conversion of PZA to POA. Mutations in the protein thereby led to PZA resistance in the bacterium due to the inefficient binding.

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Section: Methodsmentioning

confidence: 99%

Section: Receptor-ligand Interactionmentioning

confidence: 99%

Role of pncA gene mutations W68R and W68G in pyrazinamide resistance

Aggarwal

Singh

Grover

et al. 2017

J of Cellular Biochemistry

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show abstract

“…It is also possible that such mutation in the PZA binding pocket of PncA make the binding site more flexible, which allows the tight interactions between PncA mutant protein and the PZA drug that may affect the release of PZA from the binding pocket. Previous study has shown that such mutations cause the flexibility in ligand binding site that affect the drug binding …”

Section: Resultsmentioning

confidence: 99%

“…Previous study has shown that such mutations cause the flexibility in ligand binding site that affect the drug binding. 45…”

Section: Virtual Drug Screening Identified An Active Lead Compound Against Pyrazinamide Resistant M Tuberculosis Mutantsmentioning

confidence: 99%

Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutants

Jagadeb¹,

Rath²,

Sonawane³

2018

J of Cellular Biochemistry

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Emergence of multi-drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi-drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first-line anti-tuberculosis pyrazinamide (PZA) drug. First, PZA and its two isoforms were analyzed for their binding affinity toward ligand binding cavity of Mtb wild-type and mutant PncA proteins. The observations suggested that some drug resistant mutations cause strong binding of PncA with the active form of PZA and impair its release, which is required to inhibit the growth of Mtb. To improve the treatment of PZA resistant Mtb, high throughput virtual drug screening was performed to identify potent drug molecules from a library of compounds derived from ChEMBL database. From this library, we predicted a lead molecule (terta-butyl(2S,4S)-4-amino-2-cyclopropyl-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate) to be more effective against PZA resistant Mtb strains in comparison to PZA. The lead molecule showed better drug-like properties such as high affinity and atomic interactions with wild-type and drug-resistant mutations in Mtb PncA proteins. Further, molecular dynamic simulation studies showed that this lead molecule has better conformational stability and compatibility with drug-resistant PncA proteins in comparison to PZA drug. We hypothesized that the predicted lead compound could be more effective, and thus may improve the treatment of PZA resistant tuberculosis.

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In silico Analysis of Novel Mutation ala102pro Targeting pncA Gene of M. Tuberculosis

Cited by 2 publications

References 16 publications

Role of pncA gene mutations W68R and W68G in pyrazinamide resistance

Role of pncA gene mutations W68R and W68G in pyrazinamide resistance

Computational discovery of potent drugs to improve the treatment of pyrazinamide resistant Mycobacterium tuberculosis mutants

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