An extensive computational study to identify potential inhibitors of Acyl-homoserine-lactone synthase from Acinetobacter baumannii (strain AYE)

Jha, Rajat Kumar; Khan, Rameez Jabeer; Singh, Ekampreet; Kumar, Ashok; Jain, Monika; Muthukumaran, Jayaraman; Singh, Amit Kumar

doi:10.1016/j.jmgm.2022.108168

Cited by 8 publications

(6 citation statements)

References 42 publications

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“…Furthermore, the DCCM analysis was performed according to the trajectories generated from MD simulations, and the allosteric process of a protein is represented as a dynamic network of interacting residues. DCCM analysis found that Ls CR M4 shows stronger positive or negative dynamics correlations than Ls CR M3 (Figure 4c,d), suggesting an increased number of amino acids for cross‐correlated motion and more residues with stronger kinetic correlations contribute to improved thermostability (Jha et al, 2022; Parida et al, 2020). Moreover, Ls CR M4 has a higher Δ H # , implying that more bonds are required to be broken for it to reach the partially unfolded transition state (Jayawardena et al, 2017).…”

Section: Resultsmentioning

confidence: 99%

“…LsCR M4 shows stronger positive or negative dynamics correlations than LsCR M3 (Figure 4c,d), suggesting an increased number of amino acids for cross-correlated motion and more residues with stronger kinetic correlations contribute to improved thermostability (Jha et al, 2022;Parida et al, 2020). Moreover, LsCR M4 has a higher ΔH # , implying that more bonds are required to be broken for it to reach the partially unfolded transition state (Jayawardena et al, 2017).…”

Section: Mechanism Elucidation Of Thermostability Enhancementmentioning

confidence: 99%

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Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system

Liu

Weng

Zhou

et al. 2023

Biotech & Bioengineering

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Carbonyl reductase (CR)-catalyzed bioreduction in the organic phase and the neat substrate reaction system is a lasting challenge, placing higher requirements on the performance of enzymes. Protein engineering is an effective method to enhance the properties of enzymes for industrial applications. In the present work, a single point mutation E145A on our previously constructed CR mutant LsCR M3 , coevolved thermostability, and activity. Compared with LsCR M3 , the catalytic efficiency k cat /K M of LsCR M3 -E145A (LsCR M4 ) was increased from 6.6 to 21.9 s −1 mM −1 . Moreover, E145A prolonged the half-life t 1/2 at 40°C from 4.1 to 117 h, T m was increased by 5°C, T 50 30 was increased by 14.6°C, and T opt was increased by 15°C. Only 1 g/L of lyophilized Escherichia coli cells expressing LsCR M4 completely reduced up to 600 g/L 2-chloro-1-(3,4-difluorophenyl)ethanone (CFPO) within 13 h at 45°C, yielding the corresponding (1S)-2-chloro-1-(3,4-difluorophenyl)ethanol ((S)-CFPL) in 99.5% ee P , with a space-time yield of 1.0 kg/L d, the substrate to catalyst ratios (S/C) of 600 g/g.Compared with LsCR M3 , the substrate loading was increased by 50%, with the S/C increased by 14 times. Compared with LsCR WT , the substrate loading was increased by 6.5 times. In contrast, LsCR M4 completely converted 600 g/L CFPO within 12 h in the neat substrate bioreaction system.

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Section: Resultsmentioning

confidence: 99%

Section: Mechanism Elucidation Of Thermostability Enhancementmentioning

confidence: 99%

Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system

Liu

Weng

Zhou

et al. 2023

Biotech & Bioengineering

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“…The present study involves the employment of extensive computational analyses to investigate the ZINC in trial/FDA approved drug molecule library for potential drug molecules against AHLS from A. baumannii, which will disable the production of AHL molecules that eventually bring a halt to the pathway and ultimately hinders the formation and regulation of biofilms in A. baumannii. Also, we have previously studied AHLS from A. baumannii and identified promising novel lead molecules against it [12]. The present study builds on our previous study by utilising ZINC in trial/FDA approved drug molecule library to determine higher affinity under investigation/ FDA approved drug molecules against AHLS from A.…”

Section: Introductionmentioning

confidence: 91%

“…Our previous study [12] predicted the 3D structure of AHLS from A. baumannii (strain AYE) using the homology modeling approach. The experimentally solved crystal structure of TofI (PDB ID: 3P2H) from Burkholderia glumae was used as the template for SwissModel [13] based homology modeling, and the predicted model was further optimised using the YASARA energy minimisation server [14].…”

Section: Ahls Structure Predictionmentioning

confidence: 99%

Droperidol as a potential inhibitor of acyl-homoserine lactone synthase from A. baumannii: insights from virtual screening, MD simulations and MM/PBSA calculations

et al. 2022

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A. baumannii belongs to the ESKAPE family of pathogens and is a multi-drug resistant, gramnegative bacteria which follows the anaerobic form of respiration. A. baumannii is known to be the causative agent of hospital-related infections such as pneumonia, meningitis, endocarditis, septicaemia and a plethora of infections such as urinary tract and wound infections found primarily in immunocompromised patients. These attributes of A. baumannii make it a priority pathogen against which potential therapeutic agents need to be developed. A. baumannii employs the formation of a biofilm to insulate its colonies from the outer environment, which allows it to grow under harsh environmental conditions and develop resistance against various drug molecules. Acyl-homoserine lactone synthase (AHLS) is an enzyme involved in the quorum-sensing pathway in A. baumannii, which is responsible for the synthesis of signal molecules known as acyl-homoserine lactones (AHL), which trigger the signalling pathway to regulate the factors involved in biofilm formation and regulation. The current study utilised a homology modeled structure of AHLS to virtually screen it against the ZINC in trial/FDA approved drug molecule library to find a subset of potential lead molecules. These molecules were then filtered based on Lipinski's, toxicological and ADME properties, binding affinity, and interaction patterns to delineate lead molecules, which were then validated using molecular docking. The identified molecules and a control molecule were subsequently subjected to molecular dynamics simulations to mimic physiological conditions of proteinligand binding under the influence of a forcefield. The MM/PBSA based binding free energy calculations showed favourable results for Droperidol (-50.02 ± 4.67 kcal/mol) and Cipargamin (-42.29 ± 4.05 kcal/mol). The global and essential dynamics analyses, free energy landscape and dynamical cross-correlation matrix and MM/PBSA based binding free energy suggested Droperidol (ZINC000019796080) and Cipargamin (ZINC000049037032) as potential inhibitors against the acylated-ACP substrate-binding site in AHLS from A. baumannii.

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“…Among this family, A. baumannii has emerged as a pathogen of great worry pertaining to those exhibiting multi-drug resistance ( Amera, Khan, Pathak, et al., 2020b ; Jha et al., 2020 ). A. baumannii is a ubiquitously found gram-negative bacteria known to be the causative agent for hospital-acquired infections such as pneumonia, meningitis, endocarditis, septicaemia and urinary tract infections ( Amera et al., 2020c ; Jha et al., 2022 ). In addition, A. baumannii contributes to bloodstream infections in approximately 2% of all worldwide infections ( Hartzell et al., 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii – A computational study

Khan¹,

Singh²,

Jha³

et al. 2023

Current Research in Structural Biology

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An extensive computational study to identify potential inhibitors of Acyl-homoserine-lactone synthase from Acinetobacter baumannii (strain AYE)

Cited by 8 publications

References 42 publications

Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system

Coevolving stability and activity of LsCR by a single point mutation and constructing neat substrate bioreaction system

Droperidol as a potential inhibitor of acyl-homoserine lactone synthase from A. baumannii: insights from virtual screening, MD simulations and MM/PBSA calculations

Identification and prioritization of potential therapeutic molecules against LpxA from Acinetobacter baumannii – A computational study

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