Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH

Hoelz, Lucas Villas Bôas; Leal, Vinícius Fonseca; Rodrigues, Carlos Rangel; Pascutti, Pedro Geraldo; Albuquerque, Magaly Girão; Muri, Estela M.F.; Dias, Luiza R.S.

doi:10.1080/07391102.2015.1100139

Cited by 15 publications

(6 citation statements)

References 49 publications

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“…But PCA has successfully captured a clear difference in the tendency of conformational space from this limited data set . These inherent characteristics shall be reflected in a much longer and biologically relevant time scale and this hypothesis is in agreement with that fact that in vitro studies on this protein–ligand interaction have already reported the possible conformational switching. , …”

Section: Resultssupporting

confidence: 83%

“…39 These inherent characteristics shall be reflected in a much longer and biologically relevant time scale and this hypothesis is in agreement with that fact that in vitro studies on this protein−ligand interaction have already reported the possible conformational switching. 15,40 Accessible Conformational Space. It was observed that first four principal component (PC) modes comprised ∼65− 80% (Figure S5) of the overall dynamics.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Ligand Binding Swaps between Soft Internal Modes of α,β-Tubulin and Alters Its Accessible Conformational Space

Majumdar

Dastidar

2016

J. Phys. Chem. B

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The dynamic instability of the microtubule originates from the conformational switching of its building block, that is, the α, β-tubulin dimer. Ligands occupying the interface of the α-β dimer bias the switch toward the disintegration of the microtubule, which in turn controls the cell division. A little loop of tubulin is structurally encoded as a biophysical "gear" that works by changing its structural packing. The consequence of such change propagates to the quaternary level to alter the global dynamics and is reflected as a swapping between the relative contributions of dominating internal modes. Simulation shows that there is an appreciable separation between the conformational space accessed by the liganded and unliganded systems; the clusters of conformations differ in their intrinsic tendencies to "bend" and "twist". The correlation between the altered breathing modes and conformational space rationally hypothesizes a mechanism of straight-bent interconversion of the system. In this mechanism, a ligand is understood to bias the state of the "gear" that detours the conformational equilibrium away from its native preference. Thus, a fundamental biophysical insight into the mechanism of the conformational switching of tubulin is presented as a multiscale process that also shows promise to yield newer concept of ligand design.

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Section: Resultssupporting

confidence: 83%

Section: ■ Results and Discussionmentioning

confidence: 99%

Ligand Binding Swaps between Soft Internal Modes of α,β-Tubulin and Alters Its Accessible Conformational Space

Majumdar

Dastidar

2016

J. Phys. Chem. B

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“…As successfully shown by previous studies [ 26 , 27 , 28 , 29 , 30 , 31 ], MD simulations are an excellent technique to improve molecular docking results. Here, as described in the Materials and Methods section, five random replicas of 2 ns each were performed by using the Q program [ 32 ] version 6.0 [ 33 ] to provide ensembles for an improved binding process of 1,2,3-triazole-based KA into TYR.…”

Section: Resultsmentioning

confidence: 84%

Computational Analysis of Triazole-Based Kojic Acid Analogs as Tyrosinase Inhibitors by Molecular Dynamics and Free Energy Calculations

et al. 2022

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Molecular docking, molecular dynamics (MD) simulations and the linear interaction energy (LIE) method were used here to predict binding modes and free energy for a set of 1,2,3-triazole-based KA analogs as potent inhibitors of Tyrosinase (TYR), a key metalloenzyme of the melanogenesis process. Initially, molecular docking calculations satisfactorily predicted the binding mode of evaluated KA analogs, where the KA part overlays the crystal conformation of the KA inhibitor into the catalytic site of TYR. The MD simulations were followed by the LIE method, which reproduced the experimental binding free energies for KA analogs with an r2 equal to 0.97, suggesting the robustness of our theoretical model. Moreover, the van der Waals contributions performed by some residues such as Phe197, Pro201, Arg209, Met215 and Val218 are responsible for the binding recognition of 1,2,3-triazole-based KA analogs in TYR catalytic site. Finally, our calculations provide suitable validation of the combination of molecular docking, MD, and LIE approaches as a powerful tool in the structure-based drug design of new and potent TYR inhibitors.

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“…Durrant et al (2010) used sequence analysis and MD simulations to explore additional binding sites in cruzain. Hoelz et al (2016) studied free and liganded cruzain dynamics at acidic pH, which corresponds to its environment in the cell. Very recently, Cianni et al (2018) also used MD simulations to study the binding mode of reversible covalent inhibitors to the less frequently studied specific subsite S3 of cruzain.…”

Section: Cysteine Proteasesmentioning

confidence: 99%

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

Calogeropoulou¹,

Magoulas²,

Pöhner³

et al. 2019

Medicinal Chemistry of Neglected and Tropical Diseases

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The Neglected Tropical Diseases (NTDs) are a group of 17 pathologies, recognized by the World Health Organization (WHO), which are endemic in 149 countries of tropical and subtropical areas of the globe, and affect more than one billion people overall (Feasey et al. 2010). The pathologies are all caused by microparasites or macroparasites. Among the diseases provoked by microparasites, three are caused by kinetoplastidae, a group of flagellated protozoa transmitted by insect vectors: Chagas disease, Human African Trypanosomiasis and leishmaniasis. The focus of the present chapter is on the identification of new drugs for the treatment of trypanosomatidic infections such as Chagas disease, caused by Trypanosoma cruzi, and Human African Trypanosomiasis, caused by Trypanosoma brucei (Filardy et al. 2018).

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Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH

Cited by 15 publications

References 49 publications

Ligand Binding Swaps between Soft Internal Modes of α,β-Tubulin and Alters Its Accessible Conformational Space

Ligand Binding Swaps between Soft Internal Modes of α,β-Tubulin and Alters Its Accessible Conformational Space

Computational Analysis of Triazole-Based Kojic Acid Analogs as Tyrosinase Inhibitors by Molecular Dynamics and Free Energy Calculations

Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections

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