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Unraveling the Unbinding Pathways of Products Formed in Catalytic Reactions Involved in SIRT1-3: A Random Acceleration Molecular Dynamics Simulation Study
CSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0003-0185-5724
CSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India..
CSIR Cent Leather Res Inst, Inorgan & Phys Chem Lab, Chennai 600020, Tamil Nadu, India.;Acad Sci & Innovat Res AcSIR, Ghaziabad 201002, India..
2019 (English)In: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 59, no 10, p. 4100-4115Article, review/survey (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2019. Vol. 59, no 10, p. 4100-4115
Keywords [en]
Sirtuins, SIRT1, SIRT2, SIRT3, Nicotinamide, NAD(+), ADPR, Dihedral angles, Random Acceleration Molecular Dynamics Simulations, Inhibitors
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-266535DOI: 10.1021/acs.jcim.9b00513ISI: 000503918200008PubMedID: 31553614OAI: oai:DiVA.org:kth-266535DiVA, id: diva2:1391052
Note

QC 20200203

Available from: 2020-02-03 Created: 2020-02-03 Last updated: 2020-02-03Bibliographically approved

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