A5056714145- Protein Structure and Dynamics
- Enzyme Structure and Function
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- RNA and protein synthesis mechanisms
- Spectroscopy and Quantum Chemical Studies
- Computational Drug Discovery Methods
- DNA and Nucleic Acid Chemistry
- Lipid Membrane Structure and Behavior
- Chemical Synthesis and Analysis
- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- thermodynamics and calorimetric analyses
- Analytical Chemistry and Chromatography
- Crystallography and molecular interactions
- Photoreceptor and optogenetics research
- Chemical synthesis and alkaloids
- Biochemical and Molecular Research
- Monoclonal and Polyclonal Antibodies Research
- Molecular spectroscopy and chirality
- Microbial Metabolic Engineering and Bioproduction
- Bacterial Genetics and Biotechnology
- Mass Spectrometry Techniques and Applications
- Synthesis and Catalytic Reactions
- Machine Learning in Bioinformatics
Chugai Pharma (United States)
2024
Takeda (Japan)
2010-2019
The Graduate University for Advanced Studies, SOKENDAI
2003-2015
Nippon Soken (Japan)
2014
The University of Texas Medical Branch at Galveston
2013
Texas Medical Board
2013
University of Houston
2006-2011
Nagoya University
2007
Institute for Molecular Science
2004
Docking has become an indispensable approach in drug discovery research to predict the binding mode of a ligand. One great challenge docking is efficiently refine correct pose from various putative poses through scoring functions. We recently examined stability self-docking under molecular dynamics (MD) simulations and showed that equilibrium MD have some capability discriminate between decoy poses. Here, we extended our previous work cross-docking studies for practical applications. Three...
The nature in which the protecting osmolyte trimethylamine N-oxide (TMAO) and denaturing urea affect protein stability is investigated, simulating a decaalanine peptide model multiple conformations of denatured ensemble. Binary solutions both osmolytes mixed at physiologically relevant concentrations 2:1 (urea:TMAO) are studied using standard molecular dynamics simulations solvation free energy calculations. Component analysis reveals differences importance van der Waals (vdW) electrostatic...
The study of organic osmolytes has been pivotal in demonstrating the role solvent effects on protein backbone folding process. Although a thermodynamic description interactions between and osmolyte well defined, structural analysis effect incomplete. Therefore, we have performed simulations peptide model, glycine(15), protecting trimethylamine N-oxide (TMAO) solution, order to determine solution structure conformation backbone. We show that models chosen ensemble structures shifts toward...
We performed molecular dynamics simulations of urea solutions at different concentrations with two models (OPLS and KBFF) to examine the structures responsible for thermodynamic solution properties. Our simulation results showed that hydrogen-bonding properties such as average number hydrogen bonds their lifetime distributions were nearly constant all between infinite dilution solubility limit. This implies characterization urea−water in molarity concentration scale ideal is a result facile...
The transfer model implying additivity of the peptide backbone free energy is computationally tested. Molecular dynamics simulations are used to determine extent change in (DeltaG(tr)) with increase chain length oligoglycine capped end groups. Solvation energies models varying lengths pure water and osmolyte solutions, 2M urea trimethylamine N-oxide (TMAO), were calculated from all atom models, DeltaG(tr) values for solutions determined. results show that linearly increasing length,...
A novel series of pyridazinone-based phosphodiesterase 10A (PDE10A) inhibitors were synthesized. Our optimization efforts using structure-based drug design (SBDD) techniques on the basis X-ray crystal structure PDE10A in complex with hit compound 1 (IC50 = 23 nM; 110-fold selectivity over other PDEs) led to identification 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (27h). Compound 27h has potent inhibitory activity 0.30 nM), excellent...
Cyclin-dependent kinase 12 (CDK12) plays a key role in the coordination of transcription with elongation and mRNA processing. CDK12 mutations found tumors inhibition sensitize cancer cells to DNA-damaging reagents DNA-repair inhibitors. This suggests that inhibitors are potential therapeutics for may cause synthetic lethality. Here, we report discovery 3-benzyl-1-(trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel selective Structure–activity relationship studies...
Abstract We have developed a prediction method for the binding structures of ligands with proteins. Our consists three steps. First, replica‐exchange umbrella sampling simulations are performed along distance between putative site protein and ligand as reaction coordinate. Second, we obtain potential mean force (PMF) unbiased system using weighted histogram analysis determine that corresponds to global minimum PMF. Third, this global‐minimum energy values around average collected analyzed...
We have developed a two‐dimensional replica‐exchange method for the prediction of protein–ligand binding structures. The first dimension is umbrella sampling along reaction coordinate, which distance between protein pocket and ligand. second solute tempering, in interaction ligand water weakened. introduced to make follow potential more easily enhance events, should improve efficiency. As test cases, we applied our two protein‐ligand complex systems (MDM2 HSP 90‐alpha). Starting from...
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides the brain and thereby achieve potentiation nucleotide signaling pathways. This article details expedited optimization our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading discovery clinical candidate 36 (TAK-915), which demonstrates an appropriate...
We have applied our prediction method, which is based on the replica-exchange umbrella sampling for protein-ligand binding structures, to two kinase systems (p38 and JNK3) with different ligand molecules each kinase. Starting from configurations in protein are far away other, method predicted structures excellent agreement experimental data PDB all four cases, suggests general applicability of systems. In addition, flexibility was shown be essential predict correct structure one systems,...
The electrostatic (ΔGel), van der Waals cavity-formation (ΔGvdw), and total (ΔG) solvation free energies for 10 alanine peptides ranging in length (n) from 1 to monomers were calculated. computed both with fixed, extended conformations of the again some without constraints. energies, ΔGel, components ΔGvdw, ΔG, found be linear n, slopes best-fit lines being γel, γvdw, γ, respectively. Both γel γ negative fixed flexible peptides, γvdw was peptides. That surprising, as experimental data on...
We test our prediction method of membrane protein structures with glycophorin A transmembrane dimer and analyze the predicted in detail. Our consists two parts. In first part, we obtain amino-acid sequences helix regions from one existing WWW servers use them as an input for second part method. perform a replica-exchange Monte Carlo simulation these helices some constraints that indirectly represent surrounding lipid water effects identify structure global-minimum-energy state. The obtained...
Although detailed atomic models may be applied for a full description of solvation, simpler phenomenological are particularly useful to interpret the results scanning many, large, complex systems where model is too computationally expensive use. Among most costly solvation free energy evaluations by simulation. Here we develop fast way calculate electrostatic while retaining much accuracy explicit solvent The basis our method treat not as structureless dielectric continuum, but structured...
It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation cyclic nucleotide signaling pathways brain regions associated with learning memory. Following our earlier work, this article describes drug design strategy for new series lead compounds structurally distinct from clinical candidate 2 (TAK-915), subsequent medicinal...
Polytheonamide B is a linear 48-residue peptide with alternating d- and l-amino acids. It forms single β6.3-helix structure acts as cation-selective ion channel. We performed normal mode analysis to investigate the dynamical properties of polytheonamide calculated root-mean-square (RMS) displacements all backbone atoms, RMS fluctuations dihedral angles φ ψ, correlation factors for Cα atom angle fluctuations. The revealed that has elastic rod in very low-frequency modes librational motions...
A prediction method for ligand binding affinities to proteins is proposed. We first predict the structures of protein-ligand complex by replica-exchange umbrella sampling or its extension. then calculate based on these predicted ligand-protein bound double-decoupling method. As a test effectiveness proposed method, we applied it system oncoprotein MDM2 and ligand. The value affinity turned out be in good agreement with that from experiments.
Enhanced sampling yields a comprehensive structural ensemble or free energy landscape, which is beyond the capability of conventional molecular dynamics simulation. Our recently developed multiscale enhanced (MSES) method employs coarse-grained model coupled with target physical system for efficient acceleration dynamics. MSES has demonstrated applicability to large protein systems in solution, such as intrinsically disordered proteins and protein-protein protein-ligand interactions. Here,...