Correlative motions and memory effects in molecular dynamics simulations of molecules: principal components and rescaled range analysis suggest that the motions of native BPTI are more correlated than those of its mutants
“…Previously, these intramolecular motions of ligands have been almost completely ignored in drug design although the importance of intramolecular motions of proteins and other macromolecules is well approved for their biological activity. [53][54][55] The present study forms a part of our work on molecular flexibility and motions 2,47,[56][57][58] in which we have anticipated that also intramolecular motions of ligand can play a role in molecular regulation and recognition. 2 In principle, if the ligand enhances the motions of protein in the direction of reaction coordinate, it can act as an agonist, and in the other case, it can act as antagonist.…”
In this paper, the preparation and systematic evaluation of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) activities of some diaryl-1,3-diones and their synthetic intermediates, diaryl-4,5-dihydroisoxazoles, diaryl-3-hydroxyketones, diaryl-3-methoxyketones, and diaryl-2-(dimethyl-lambda 4-sulfanylidene)-1,3-diones, is described. The set of 72 compounds constitutes a general schematic structure aryl1-linker1-spacer-linker2-aryl2, where the linker1-spacer-linker2 length varies between 4 and 8 carbons. The set of compounds was applied here to map and explore the active sites of subtypes ER alpha and ER beta. The highest activities were obtained with dihydroisoxazole and hydroxyketone spacers, but even the most flexible diones with unsubstituted aryl groups showed some agonism. Most compounds were found to be ER alpha selective or to activate both receptors, but in some cases we saw also clearly stronger ER beta activation.
“…Previously, these intramolecular motions of ligands have been almost completely ignored in drug design although the importance of intramolecular motions of proteins and other macromolecules is well approved for their biological activity. [53][54][55] The present study forms a part of our work on molecular flexibility and motions 2,47,[56][57][58] in which we have anticipated that also intramolecular motions of ligand can play a role in molecular regulation and recognition. 2 In principle, if the ligand enhances the motions of protein in the direction of reaction coordinate, it can act as an agonist, and in the other case, it can act as antagonist.…”
In this paper, the preparation and systematic evaluation of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) activities of some diaryl-1,3-diones and their synthetic intermediates, diaryl-4,5-dihydroisoxazoles, diaryl-3-hydroxyketones, diaryl-3-methoxyketones, and diaryl-2-(dimethyl-lambda 4-sulfanylidene)-1,3-diones, is described. The set of 72 compounds constitutes a general schematic structure aryl1-linker1-spacer-linker2-aryl2, where the linker1-spacer-linker2 length varies between 4 and 8 carbons. The set of compounds was applied here to map and explore the active sites of subtypes ER alpha and ER beta. The highest activities were obtained with dihydroisoxazole and hydroxyketone spacers, but even the most flexible diones with unsubstituted aryl groups showed some agonism. Most compounds were found to be ER alpha selective or to activate both receptors, but in some cases we saw also clearly stronger ER beta activation.
“…The same force field used in the MD simulations was used in the free energy calculations. The entropy contribution to the binding free energy was neglected because it has been shown that it mostly cancels when it is estimated from the same set of coordinates for the protein, ligand, and the protein/ligand complex. − …”
Section: Methodsmentioning
confidence: 99%
“…PCA can be used to simplify a large set of data by decreasing the number of variables using multivariate analysis. PCA has been used to analyze the structures from MD simulations and has been previously described in detail. − 1 Potential energies during the molecular dynamics simulation for the three systems studied: (A) wild-type RT/nevirapine; (B) mutant RT/nevirapine; (C) unliganded RT.…”
Section: Methodsmentioning
confidence: 99%
“…The entropy contribution to the binding free energy was neglected because it has been shown that it mostly cancels when it is estimated from the same set of coordinates for the protein, ligand, and the protein/ligand complex. [61][62][63][64][65][66][67][68][69][70] Principal Component Analysis (PCA). PCA can be used to simplify a large set of data by decreasing the number of variables using multivariate analysis.…”
Section: Methodsmentioning
confidence: 99%
“…PCA has been used to analyze the structures from MD simulations and has been previously described in detail. [61][62][63][64][65][66][67][68][69][70][71] A symmetric matrix A with elements equal to the pairwise RMS coordinate difference between superimposed structures along the trajectory is employed in this work:…”
HIV-1 reverse transcriptase (RT) is an important target for drugs used in the treatment of AIDS. Drugs known as non-nucleoside RT inhibitors (NNRTI) appear to alter the structural and dynamical properties of RT which in turn inhibit RT's ability to transcribe. Molecular dynamics (MD), principal component analysis (PCA), and binding free energy simulations are employed to explore the dynamics of RT and its interaction with the bound NNRTI nevirapine, for both wild-type and mutant (V106A, Y181C, Y188C) RT. These three mutations commonly arise in the presence of nevirapine and result in resistance to the drug. We show that a bound NNRTI hinders the motion of almost all RT amino acids. The mutations, located in the non-nucleoside RT inhibitor binding pocket, partially restore RT flexibility. The binding affinities calculated by molecular mechanics/Poisson-Boltzmann surface accessibility (MM-PBSA) show that nevirapine interacts stronger with wild-type RT than with mutant RT. The mutations cause a loss of van der Waals interactions between the drug and the binding pocket. The results from this study suggest that a good inhibitor should efficiently enter and maximally occupy the binding pocket, thereby interacting effectively with the amino acids around the binding pocket.
Molecular dynamics simulations were carried out for the mutant oseltamivir-NA complex, to provide detailed information on the oseltamivir-resistance resulting from the H274Y mutation in neuraminidase (NA) of avian influenza H5N1 viruses. In contrast with a previous proposal, the H274Y mutation does not prevent E276 and R224 from forming the hydrophobic pocket for the oseltamivir bulky group. Instead, reduction of the hydrophobicity and size of pocket in the area around an ethyl moiety at this bulky group were found to be the source of the oseltamivir-resistance. These changes were primarily due to the dramatic rotation of the hydrophilic -COO(-) group of E276 toward the ethyl moiety. In addition, hydrogen-bonding interactions with N1 residues at the -NH(3) (+) and -NHAc groups of oseltamivir were replaced by a water molecule. The calculated binding affinity of oseltamivir to NA was significantly reduced from -14.6 kcal mol(-1) in the wild-type to -9.9 kcal mol(-1) in the mutant-type.
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