In-silico screening and validation of high-affinity tetra-peptide inhibitor of <i>Leishmania donovani</i> O-acetyl serine sulfhydrylase (OASS)

Kant, Vishnu; Vijayakumar, Saravanan; Sahoo, Ganesh Chandra; Ali, Vahab; Singh, Kuljit; Chaudhery, Shailendra S.; Das, Pradeep

doi:10.1080/07391102.2018.1429315

Cited by 12 publications

(13 citation statements)

References 34 publications

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“…The binding affinity between different tubulin isotypes and TauR2 was explored by performing relative binding energy calculation similar to earlier studies 67–69 . The stable region of the trajectory observed in between 70 ns to 100 ns and hence we extracted 70–100 ns trajectory to perform the binding energy calculations for all the tubulin-TauR2 complexes.…”

Section: Methodsmentioning

confidence: 99%

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Differential binding affinity of tau repeat region R2 with neuronal-specific β-tubulin isotypes

Bhandare

Kumbhar

Kunwar

2019

Sci Rep

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Tau is a microtubule-associated protein whose C-terminal domain consisting of four repeat regions R1, R2, R3 and R4 binds to microtubules to stabilize them. In several neurodegenerative diseases, tau detaches from microtubules to form insoluble aggregates leading to tauopathy. Microtubules are made up of αβ tubulin subunits. Seven α-tubulin and nine β-tubulin isotypes have been reported to be present in humans till date. These tubulin isotypes show residue composition variations mainly at C-terminal region and bind to motor proteins and anti-mitotic drugs differently. These tubulin isotypes show tissue specific expression as their relative proportion varies significantly in different type of cells. It is also known that tau binds differently to different cell lines and can either promote or demote microtubule polymerization. However, the relative binding affinity of tau to the different β-tubulin isotypes present in different cell lines is completely unknown. Here, we study relative binding affinity of Tau repeat region R2 to neuronal specific tubulin isotypes βI, βIIb, and βIII using molecular modelling approach. The order of binding energy of tau with tubulin is βIII > βIIb > βI. Our strategy can be potentially adapted to understand differential binding affinity of tau towards β-tubulin isotypes present in other cell lines.

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Section: Methodsmentioning

confidence: 99%

“…The tool ‘g_mmpbsa’ v1.6 was used to calculate binding energy using MM/PBSA approach 70 implemented in gromacs 2018.1. The parameters for binding energy calculations were taken from the earlier similar studies 59,69,71–73 . The binding energy (ΔG bind ) of tubulin and TauR2 was calculated by using the following Eq.…”

Section: Methodsmentioning

confidence: 99%

Differential binding affinity of tau repeat region R2 with neuronal-specific β-tubulin isotypes

Bhandare

Kumbhar

Kunwar

2019

Sci Rep

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“…Here, the binding affinity between different neuronal specific tubulin isotypes and TauR2 was estimated by performing relative binding energy calculation similar to earlier studies [63][64][65]. The stable trajectory observed in between 70 ns to 100 ns was chosen to perform the binding energy calculations for all the tubulin-TauR2 complexes.…”

Section: Binding Affinity Of Taur2 Towards Different Neuronal Specifimentioning

confidence: 99%

“…The 'g_mmpbsa' tool v1.6 was used to perform binding energy calculation using MM/PBSA approach [66]. The parameters for the binding energy calculations were chosen from the earlier similar studies [52,65,[67][68][69]…”

Section: Binding Affinity Of Taur2 Towards Different Neuronal Specifimentioning

confidence: 99%

Homology Modeling of Tubulin Isotypes to Investigate MT-Tau Interactions

Bhandare¹

2021

Homology Molecular Modeling - Perspectives and Applications

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The Homology modeling techniques uses the template structure(s) to model the full-length structure of unknown sequence. It is being used for determining the structure of biological macromolecules, especially proteins. The wide applications of homology modeling approach have helped us to address various challenging problems in the field of biological sciences and drug discovery despite the limitations in using analytical techniques like X-ray, NMR and CryoEM techniques. Here, this chapter emphasize on application of homology modeling in determining MT-Tau interactions which are important in the Alzheimer disease. In Alzheimer diseases, tau detaches from MTs in misfolded shape and forms insoluble aggregates in neurons due to post-translational modifications. MT-tau interactions are largely unknown due to differential expression of neuronal specific tubulin isotypes and intrinsically disordered nature of tau. MTs play crucial roles in important cellular functions including cell division, transport of vesicles, cell signaling, cell motility etc. MTs are composed of different tubulin isotypes which differs mainly at C-terminal tail. In humans, nine β-tubulin isotypes have been reported which are expressed differently in different tissues. Structures for different tubulin isotypes are still lacking due to their complex differential expression pattern and purification. Hence, homology modeling approach allowed us to generate homology models for different neuronal specific tubulin isotypes and study their interactions with tau repeats. It is believed that this study would gain more structural and functional insights to the linked Alzheimer diseases.

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“…These structural determinants extracted from crystal structures of various peptide-enzyme complexes formed the basis for developing peptide/nonpeptide inhibitors. Since then several studies have reported inhibitors against open conformation of CysK from different organisms with affinities for CysK generally ranging from millimolar to micromolar concentrations (Jean Kumar et al 2013;Spyrakis et al 2013;Yadava et al 2015;Kant et al 2018). Natural compounds as potential inhibitors of CysK have also been reported, however, the leads from these studies require rational modifications to achieve better efficacy (Nagpal et al 2012;Mori et al 2015Mori et al , 2018.…”

Section: Inhibition By the Endogenous Cyse Peptidementioning

confidence: 99%

Insights into multifaceted activities of CysK for therapeutic interventions

Joshi

Gupta

2019

3 Biotech

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CysK (O-acetylserine sulfhydrylase) is a pyridoxal-5′ phosphate-dependent enzyme which catalyzes the second step of the de novo cysteine biosynthesis pathway by converting O-acetyl serine (OAS) into l-cysteine in the presence of sulfide. The first step of the cysteine biosynthesis involves formation of OAS from serine and acetyl CoA by CysE (serine acetyltransferase). Apart from role of CysK in cysteine biosynthesis, recent studies have revealed various additional roles of this enzyme in bacterial physiology. Other than the suggested regulatory role in cysteine production, other activities of CysK include involvement of CysK-in contact-dependent toxin activation in Gram-negative pathogens, as a transcriptional regulator of CymR by stabilizing the CymR-DNA interactions, in biofilm formation by providing cysteine and via another mechanism not yet understood, in ofloxacin and tellurite resistance as well as in cysteine desulfurization. Some of these activities involve binding of CysK to another cellular partner, where the complex is regulated by the availability of OAS and/or sulfide (H 2 S). The aim of this study is to present an overview of current knowledge of multiple functions performed by CysK and identifying structural features involved in alternate functions. Due to possible role in disease, promoting or inhibiting a "moonlighting" function of CysK could be a target for developing novel therapeutic interventions.

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In-silico screening and validation of high-affinity tetra-peptide inhibitor of Leishmania donovani O-acetyl serine sulfhydrylase (OASS)

Cited by 12 publications

References 34 publications

Differential binding affinity of tau repeat region R2 with neuronal-specific β-tubulin isotypes

Differential binding affinity of tau repeat region R2 with neuronal-specific β-tubulin isotypes

Homology Modeling of Tubulin Isotypes to Investigate MT-Tau Interactions

Insights into multifaceted activities of CysK for therapeutic interventions

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