Unraveling the Unbinding Pathways of Products Formed in Catalytic Reactions Involved in SIRT1-3: A Random Acceleration Molecular Dynamics Simulation Study

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Muvva, CharuvakaCSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India. (författare)

Unraveling the Unbinding Pathways of Products Formed in Catalytic Reactions Involved in SIRT1-3 : A Random Acceleration Molecular Dynamics Simulation Study

Artikel/kapitelEngelska2019

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2019-09-25
AMER CHEMICAL SOC,2019
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LIBRIS-ID:oai:DiVA.org:kth-266535
https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-266535URI
https://doi.org/10.1021/acs.jcim.9b00513DOI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:for swepub-publicationtype

Anmärkningar

QC 20200203
Sirtuins are a family of nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes, which undergo robust deacetylase activity, resulting in the production of nicotinamide. It is well known that nicotinamide, which is one of the products, can also act as an inhibitor for further deacetylation process by forming NAD(+) again. Hence, the removal of nicotinamide from sirtuins is a demanding process, and the mechanistic understanding of the process remains elusive. In this investigation, we have made an attempt to unravel the unbinding pathways of nicotinamide from SIRT1, SIRT2, and SIRT3 (SIRT1-3) using Random Acceleration Molecular Dynamics (RAMD) Simulations, and we have successfully identified various unbinding channels. The selectivity of the egression channel is determined by using a thorough analysis of the frequency of egression trajectories. Similarly, various inhibitors have been docked with the active sites of SIRT1-3, and their egression pathways have been investigated to understand whether they follow the same egression pathway as that of nicotinamide. The residues that are responsible for the unbinding pathways have been determined from the analysis of RAMD trajectories. From these results, it is clear that phenylalanine and histidine residues play major roles in the egression of inhibitors. Additionally, the key residues Leu, Pro, Met, Phe, Tyr, and Ile are found to control the release by acting as gateway residues. The role of these residues from different egression channels has been studied by carrying out mutations with alanine residue. This is the first report on sirtuins, which demonstrates the novel unbinding pathways for nicotinamide/inhibitors. This work provides new insights for developing more promising SIRT1-3 inhibitors.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Läkemedelskemi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Medicinal Chemistry hsv//eng
Sirtuins
SIRT1
SIRT2
SIRT3
Nicotinamide
NAD(+)
ADPR
Dihedral angles
Random Acceleration Molecular Dynamics Simulations
Inhibitors

Biuppslag (personer, institutioner, konferenser, titlar ...)

Natarajan Arul, MuruganKTH,Teoretisk kemi och biologi(Swepub:kth)u1tv6j3w (författare)
Choutipalli, Venkata Surya KumarCSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India. (författare)
Subramanian, VenkatesanCSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India. (författare)
CSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India.Teoretisk kemi och biologi (creator_code:org_t)

Sammanhörande titlar

Ingår i:Journal of Chemical Information and Modeling: AMER CHEMICAL SOC59:10, s. 4100-41151549-95961549-960X

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