Search results for "molecular dynamics simulation"
showing 10 items of 260 documents
Binding isotope effects as a tool for distinguishing hydrophobic and hydrophilic binding sites of HIV-1 RT.
2014
The current treatment for HIV-1 infected patients consists of a cocktail of inhibitors, in an attempt to improve the potency of the drugs by adding the possible effects of each supplied compound. In this contribution, nine different inhibitors of HIV-1 RT, one of the three key proteins responsible for the virus replication, have been selected to develop and test a computational protocol that allows getting a deep insight into the inhibitors’ binding mechanism. The interaction between the inhibitors and the protein have been quantified by computing binding free energies through FEP calculations, while a more detailed characterization of the kind of inhibitor–protein interactions is based on …
Molecular topology applied to the discovery of 1-benzyl-2-(3-fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole-5-one as a non-ligand-binding-p…
2014
We report the discovery of 1-benzyl-2-(3- fluorophenyl)-4-hydroxy-3-(3-phenylpropanoyl)-2H-pyrrole- 5-one as a novel non-ligand binding pocket (non-LBP) antagonist of the androgen receptor (AR) through the application of molecular topology techniques. This compound, validated through time-resolved fluorescence resonance energy transfer and fluorescence polarization biological assays, provides the basis for lead optimization and structure−activity relationship analysis of a new series of non-LBP AR antagonists. Induced-fit docking and molecular dynamics studies have been performed to establish a consistent hypothesis for the interaction of the new active molecule on the AR surface. Refereed/…
Peptide Metal–Organic Frameworks for Enantioselective Separation of Chiral Drugs
2017
We report the ability of a chiral Cu(II) 3D MOF based on the tripeptide Gly-L-His-Gly (GHG) for the enantioselective separation of metamphetamine and ephedrine. Monte Carlo simulations suggest that chiral recognition is linked to preferential binding of one of the enantiomers as result of either stronger or additional H-bonds with the framework that lead to energetically more stable diastereomeric adducts. Solid phase extraction (SPE) of a racemic mixture by using Cu(GHG) as extractive phase permits isolating more than 50% of the (+)-ephedrine enantiomer as target compound in only four minutes. To the best of our knowledge, this represents the first example of a MOF capable of separating ch…
Hypoxia-Selective Dissociation Mechanism of a Nitroimidazole Nucleoside in a DNA Environment
2019
Photodynamic therapy is a promising approach to treat a variety of superficial tumors and other diseases. One of its major limitations arises from its dependence on molecular oxygen, which decreases the efficiency of the therapy in hypoxia conditions commonly developed by solid tumors. The present contribution reveals the molecular mechanism of a modified thymine bearing a nitroimidazole substituent, a photosensitizer able to produce highly harmful interstrand cross-links in the DNA double strand after irradiation selectively in absence of oxygen. The mechanism is resolved at a fully atomistic and electronic level relying on quantum mechanics (CASPT2, coupled-cluster, DFT, and TD-DFT method…
Structure and Dynamics of the Instantaneous Water/Vapor Interface Revisited by Path-Integral and Ab Initio Molecular Dynamics Simulations
2015
The structure and dynamics of the water/vapor interface is revisited by means of path-integral and second-generation Car-Parrinello ab-initio molecular dynamics simulations in conjunction with an instantaneous surface definition [A. P. Willard and D. Chandler, J. Phys. Chem. B 114, 1954 (2010)]. In agreement with previous studies, we find that one of the OH bonds of the water molecules in the topmost layer is pointing out of the water into the vapor phase, while the orientation of the underlying layer is reversed. Therebetween, an additional water layer is detected, where the molecules are aligned parallel to the instantaneous water surface.
Quantifying the limits of transition state theory in enzymatic catalysis
2017
Significance Transition state theory (TST) is the most popular theory to calculate the rates of enzymatic reactions. However, in some cases TST could fail due to the violation of the nonrecrossing hypothesis at the transition state. In the present work we show that even for one of the most controversial enzymatic reactions—the hydride transfer catalyzed by dihydrofolate reductase—the error associated to TST represents only a minor correction to the reaction rate. Moreover, this error is actually larger for the reaction in solution than in the enzymatic active site. Based on this finding and on previous studies we propose an “enzymatic shielding” hypothesis which encompasses various aspects …
The mechanism of aquaporin inhibition by gold compounds elucidated by biophysical and computational methods
2017
The inhibition of water and glycerol permeation via human aquaglyceroporin-3 (AQP3) by gold(iii) complexes has been studied by stopped-flow spectroscopy and, for the first time, its mechanism has been described using molecular dynamics (MD), combined with density functional theory (DFT) and electrochemical studies. The obtained MD results showed that the most effective gold-based inhibitor, anchored to Cys40 in AQP3, is able to induce shrinkage of pores preventing glycerol and water permeation. Moreover, the good correlation between the affinity of the Au(iii) complex to Cys binding and AQP3 inhibition effects was highlighted, while no influence of the different oxidative character of the c…
Inhibitor-Induced Dimerization of an Essential Oxidoreductase from African Trypanosomes
2018
Trypanosomal and leishmanial infections claim tens of thousands of lives each year. The metabolism of these unicellular eukaryotic parasites differs from the human host and their enzymes thus constitute promising drug targets. Tryparedoxin (Tpx) from Trypanosoma brucei is the essential oxidoreductase in the parasite's hydroperoxide-clearance cascade. In vitro and in vivo functional assays show that a small, selective inhibitor efficiently inhibits Tpx. With X-ray crystallography, SAXS, analytical SEC, SEC-MALS, MD simulations, ITC, and NMR spectroscopy, we show how covalent binding of this monofunctional inhibitor leads to Tpx dimerization. Intra- and intermolecular inhibitor-inhibitor, pro…
NMR structure of a non-conjugatable, ADP-ribosylation associated, ubiquitin-like domain from Tetrahymena thermophila polyubiquitin locus.
2019
Abstract Background Ubiquitin-like domains (UbLs), in addition to being post-translationally conjugated to the target through the E1-E2-E3 enzymatic cascade, can be translated as a part of the protein they ought to regulate. As integral UbLs coexist with the rest of the protein, their structural properties can differ from canonical ubiquitin, depending on the protein context and how they interact with it. In this work, we investigate T.th-ubl5, a UbL present in a polyubiquitin locus of Tetrahymena thermophila, which is integral to an ADP-ribosyl transferase protein. Only one other co-occurrence of these two domains within the same protein has been reported. Methods NMR, multiple sequence al…
A Molecular Dynamics-Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Rec…
2016
Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein's active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activat…