Biomedical subjects

Danzhi Huang

Publications and source records attributed to Danzhi Huang.

6 recordsLinked to original sources

PubMed2006

In silico discovery of beta-secretase inhibitors.

Alzheimer's disease, the most common amyloid-associated disorder, accounts for the majority of the dementia diagnosed after the age of 60. The cleavage of the beta-amyloid precursor protein is initiated by beta-secretase (BACE-1), a membrane-bound aspartic protease, which has emerged as an important but difficult protein target. Here, an in silico screening approach consisting of fragment-based docking, ligand conformational search by a genetic algorithm, and evaluation of free energy of binding was used to identify low-molecular-weight inhibitors of BACE-1. More than 300,000 small molecules were docked and about 15,000 prioritized according to a linear interaction energy model with evaluation of solvation by continuum electrostatics. Eighty-eight compounds were tested in vitro, and 10 of them showed an IC(50) value lower than 100 microM in a BACE-1 enzymatic assay. Interestingly, the 10 active compounds shared a triazine scaffold. Moreover, four of them were active in an assay with mammalian cells (EC(50) < 20 microM), indicating that they are cell-permeable. Therefore, these triazine derivatives are very promising lead candidates for BACE-1 inhibition. The discoveries of this series and two other series of nonpeptidic BACE-1 inhibitors demonstrate the usefulness of our in silico high-throughput screening approach.

Amyloid Precursor Protein Secretases↗

PubMed2005

Discovery of cell-permeable non-peptide inhibitors of beta-secretase by high-throughput docking and continuum electrostatics calculations.

A fragment-based docking procedure followed by substructure search were used to identify active-site beta-secretase inhibitors from a composite set of about 300 000 and a library of nearly 180 000 small molecules, respectively. EC(50) values less than 10 microM were measured in at least one of two different mammalian cell-based assays for 12 of the 72 purchased compounds. In particular, the phenylureathiadiazole 2 and the diphenylurea derivative 3 are promising lead compounds for beta-secretase inhibition.

Amyloid Precursor Protein Secretases↗

PubMed2005

Nonuniform charge scaling (NUCS): a practical approximation of solvent electrostatic screening in proteins.

In molecular mechanics calculations, electrostatic interactions between chemical groups are usually represented by a Coulomb potential between the partial atomic charges of the groups. In aqueous solution these interactions are modified by the polarizable solvent. Although the electrostatic effects of the polarized solvent on the protein are well described by the Poisson--Boltzmann equation, its numerical solution is computationally expensive for large molecules such as proteins. The procedure of nonuniform charge scaling (NUCS) is a pragmatic approach to implicit solvation that approximates the solvent screening effect by individually scaling the partial charges on the explicit atoms of the macromolecule so as to reproduce electrostatic interaction energies obtained from an initial Poisson--Boltzmann analysis. Once the screening factors have been determined for a protein the scaled charges can be easily used in any molecular mechanics program that implements a Coulomb term. The approach is particularly suitable for minimization-based simulations, such as normal mode analysis, certain conformational reaction path or ligand binding techniques for which bulk solvent cannot be included explicitly, and for combined quantum mechanical/molecular mechanical calculations when the interface to more elaborate continuum solvent models is lacking. The method is illustrated using reaction path calculations of the Tyr 35 ring flip in the bovine pancreatic trypsin inhibitor.

Algorithms↗

PubMed2004

Efficient evaluation of binding free energy using continuum electrostatics solvation.

The linear interaction energy (LIE) method is combined with energy minimization and finite-difference Poisson calculation of electrostatic solvation for the estimation of the absolute free energy of binding. A predictive accuracy of about 1.0 kcal/mol is obtained for 13 and 29 inhibitors of beta-secretase (BACE) and HIV-1 protease (HIV-1 PR), respectively. The multiplicative coefficients for the van der Waals and electrostatic terms are not transferable between BACE and HIV-1 PR although they are both aspartic proteases. The present approach is about 2 orders of magnitude faster than previous LIE methods and can be used for ranking large libraries of structurally diverse compounds docked by automatic computational tools.

Amyloid Precursor Protein Secretases↗

PubMed2003

How well does charge reparametrisation account for solvent screening in molecular mechanics calculations? The example of myosin.

The rate constant of an enzyme-catalysed reaction is one of the major target properties to understand protein function. Atomic-detail computer simulations can in principle be used to estimate rate constants from the energy profile along the reaction coordinate. For such simulations, molecular mechanics is combined with a quantum description of the reaction process. In molecular mechanics calculations, the electrostatic field is represented by the Coulomb potential of partial atomic charges which have been parametrised for small building blocks in vacuum and transferred to the macromolecule. In aqueous solution, however, the electrostatic interactions are affected by the solvent polarization. While this can be described by numerically solving the Poisson-Boltzmann equation, it is computationally expensive. A simple approximation to this is to optimally reproduce the electrostatic potential in solution by reparametrising the partial atomic charges in such a way that a simple Coulomb potential can still be used. Such a procedure would allow to perform fast calculations of reaction processes in proteins while accounting for the solvent screening effect. Here, this method is tested on myosin, a motor protein that is both an enzyme and exists in very different conformations.

Adenosine Triphosphate↗

PubMed2003

Time-resolved computational protein biochemistry: solvent effects on interactions, conformational transitions and equilibrium fluctuations.

Solvent plays an important role in modulating internal motions of proteins. Here we present a computational method for including solvent effects on charge-charge interactions and on pathways between functional protein conformations, and examine solvent effects on equilibrium internal fluctuations in proteins. A computationally efficient charge reparametrisation method is presented that satisfactorily reproduces the electrostatic interactions present in a full continuum Poisson-Boltzmann representation. The application of charge reparametrisation in the calculation of a large-scale conformational transition pathway in a protein, annexin V, is illustrated. We also examine solvent effects on fast (picosecond timescale) internal protein dynamics. Nosé-Hoover dual heatbath molecular dynamics simulations are performed. These simulations allow the solvent region to be fixed at one temperature and the protein at another. The results of the Nosé-Hoover simulations on hydrated myoglobin confirm that the solvent temperature strongly influences the protein fluctuations. We consider to what extent the solvent can be considered to determine the high temperature protein dynamics.

Animals↗