Structural Dynamics of DPP-4 and Its Influence on the Projection of Bioactive Ligands

Pantaleão, Simone Queiroz; Philot, Eric Allison; Resende-Lara, Pedro T.; Lima, Angélica Nakagawa; Pérahia, David; Miteva, Maria A.; Scott, Ana Lígia; Honório, Káthia Maria

doi:10.3390/molecules23020490

Cited by 34 publications

(24 citation statements)

References 35 publications

(87 reference statements)

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“…Molecular dynamics (MD) simulations 29 and more recent Normal Mode Analysis approaches 30 , 31 have become major techniques in the arsenal of tools developed to investigate the mode of action of bioactive molecules. A recent approach called MDeNM (molecular dynamics with excited normal modes) has recently been developed using low-frequency normal mode directions in MD simulations 32 .…”

Section: Introductionmentioning

confidence: 99%

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

Dudas

Tóth

Pérahia

et al. 2021

Sci Rep

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Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein–ligand interactions studies where major rearrangements are expected.

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Section: Introductionmentioning

confidence: 99%

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

Dudas

Tóth

Pérahia

et al. 2021

Sci Rep

Self Cite

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“…In chain B, it is evident that the substrate binding region and the catalytic dyad of the mutants presented, on average, a higher flexibility in comparison to the wild-type molecule. This asymmetric/distinct behavior between the chains in homodimeric enzymes were also identified by molecular dynamics simulations involving the SARS-CoV-2 M pro [17] and SARS-CoVM pro [41] as well as NMA calculation for HIV-1 protease [42] and DPP-IV diabetes related protein [43]. Thus, this analysis indicated that some mutants may present characteristics that can influence their catalytic activity, substrate binding affinity and/or dimer stability, as also shown previously by Amamuddy et al (2020) [17].…”

Section: Resultsmentioning

confidence: 61%

Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

Philot

Gasparini

Mattos

et al. 2021

Preprint

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In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties.

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“…Moreover, K. M. Honorio et al utilized dynamic protein methods to design human DPP4 inhibitors that might fit into the catalytic region. The study shows that human DPP4 functional motion significantly affects the design of such inhibitors (Pantaleão, 2018;Ribeiro & Filizola, 2019). Further, structural and modeling studies of human ACE2 suggest spatial interactions with SARS-CoV-2 might be varied among COVID-19 patients due to genetic variants in ACE2, which leads to susceptibility variations against the virus (Hussain, 2020).…”

Section: Introductionmentioning

confidence: 90%

Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

Alaofi

2020

Journal of Biomolecular Structure and Dynamics

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Mouse DPP4 (mDPP4) receptor is not a functional receptor for MERS-CoV while human DPP4 (hDPP4) is, despite the high similarities between hDPP4 and mDPP4 receptors. The variability of DPP4 receptors against MERS-CoV is not fully investigated, especially conformational and structural differences. Therefore, investigating the conformational differences of the DPP4 receptors can aid in developing new small animal models for MERS-CoV vaccines and antiviral agents evaluation. Here we used MD simulations and docking techniques to investigate these structural differences in DPP4 receptors. The results showed chimeric mouse mDPP4 (cmDPP4) has a similar compact conformation as wild-type hDPP4 based on the structural analysis. Interestingly, a single Thr288Ala mutation induced a relaxed conformation in chimeric 2 hDPP4 (c2hDPP4) and chimeric 2 mDPP4 (c2mDPP4); in addition to its significant effect on the DPP4 flexibility. The Thr288 residue is known for its critical function in MERS-CoV RBD interaction. Moreover, MERS-CoV RBD adopts a "standing" conformation when docked to hDPP4 and cmDPP4 in blade IV and V regions. In conclusion, the results could explain the functionality differences between mouse and human DPP4 receptors against MERS-CoV. However, further structural studies are needed to evaluate how DPP4 conformations affects MERS-CoV RBD binding and affinity.

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Structural Dynamics of DPP-4 and Its Influence on the Projection of Bioactive Ligands

Cited by 34 publications

References 35 publications

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations

Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

Exploring structural dynamics of the MERS-CoV receptor DPP4 and mutant DPP4 receptors

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