Presentation is loading. Please wait.

Presentation is loading. Please wait.

Richard S. L. Stein CS 379a March 14, 2006

Published byAgus Tedjo Modified over 6 years ago

Similar presentations

Presentation on theme: "Richard S. L. Stein CS 379a March 14, 2006"— Presentation transcript:

1 Richard S. L. Stein CS 379a March 14, 2006
A Multistep Approach to Structure-Based Drug Design: Studying Ligand Binding at the Human Neutrophil Elastase (T. Steinbrecher, D. A. Case, and A. Labahn) Richard S. L. Stein CS 379a March 14, 2006

2 Modeling of HNE Inhibition
Overabundance of human neutrophile elastase (HNE) degrades healthy tissue and results in various diseases Inhibitory action on HNE modeled by ligand docking calculations and molecular dynamics (MD) simulations of several known inhibitors of HNE; structure dynamics analyzed by MM-PBSA method MD runs of 2 ns exhibited instability of many ligand-protein complexes Binding free energies from MD simulations disagreed with experiment The two most effective binding ligands, bornyl caffeate & fukinolic acid, were each given 30 docking placements divided into groups according to docking formation

3 Bornyl Caffeate & Fukinolic Acid (color = distinct placement within HNE)

4 Docking Configuration Analysis
MD simulation runs of 1 ns were performed on placement groups for bornyl caffeate and fukinolic acid, and closely related compounds Most stable ligand-protein complexes were further analyzed by thermodynamic integration (TI) calculations Binding free energies agreed with experiment better with bornyl caffeate derivatives than with fukinolic acid derivatives MD simulation analysis of bornyl caffeate—HNE complex found a prospective binding mode Bornyl ferulate (a bornyl caffeate derivative) was found to bind more strongly to HNE with the transfer of a ring OH group Caffeic acid was found to bind significantly more weakly to HNE than bornyl caffeate, indicating importance of ligand hydrophobicity

5 Advantages & Drawbacks
Combination of techniques (ligand docking, MD simulation and TI calculations) discovered a possible binding mode within HNE for bornyl caffeate Ability to propose binding modes for bornyl caffeate derivatives (ex. one conformation of bornyl ferulate) Drawbacks: Failure to find binding mode for a good HNE inhibitor (fukinolic acid and its derivatives) MM-PBSA has statistical error (1 kcal/mol) equal to differences in binding free energies of similar placements for differing ligands (1—2 kcal/mol) Length of simulations: could more reliable ligand-protein complex stability data be obtained for runs longer than 1 ns?

Download ppt "Richard S. L. Stein CS 379a March 14, 2006"

Similar presentations

Combinatorial computational method gives new picomolar ligands for a known enzyme Bartosz A. Grzybowski, Alexey V. Ishchenko, Chu- Young Kim, George Topalov,

Combinatorial computational method gives new picomolar ligands for a known enzyme Bartosz A. Grzybowski, Alexey V. Ishchenko, Chu- Young Kim, George Topalov,
Evaluating Free Energies of Binding using Amber: The MM-PBSA Approach.

Evaluating Free Energies of Binding using Amber: The MM-PBSA Approach.
EDTA Titrations. Chelation in Biochemistry Chelating ligands can form complex ions with metals through multiple ligands. This is important in many areas,

EDTA Titrations. Chelation in Biochemistry Chelating ligands can form complex ions with metals through multiple ligands. This is important in many areas,
Ion Solvation Thermodynamics from Simulation with a Polarizable Force Field Gaurav Chopra 07 February 2005 CS 379 A Alan GrossfeildPengyu Ren Jay W. Ponder.

Ion Solvation Thermodynamics from Simulation with a Polarizable Force Field Gaurav Chopra 07 February 2005 CS 379 A Alan GrossfeildPengyu Ren Jay W. Ponder.
Molecular dynamics refinement and rescoring in WISDOM virtual screenings Gianluca Degliesposti University of Modena and Reggio Emilia Molecular Modelling.

Molecular dynamics refinement and rescoring in WISDOM virtual screenings Gianluca Degliesposti University of Modena and Reggio Emilia Molecular Modelling.
 Structure-based drug design:  The macromolecular target can be isolated and crystallized…then the structure will be determined using X-ray crystallography.

 Structure-based drug design:  The macromolecular target can be isolated and crystallized…then the structure will be determined using X-ray crystallography.
1. Free energy with controlled uncertainty 2. The modes of ligand binding to DNA Tomáš Kubař Institute of Organic Chemistry and Biochemistry Praha, Czech.

1. Free energy with controlled uncertainty 2. The modes of ligand binding to DNA Tomáš Kubař Institute of Organic Chemistry and Biochemistry Praha, Czech.
Case Studies Class 5. Computational Chemistry Structure of molecules and their reactivities Two major areas –molecular mechanics –electronic structure.

Case Studies Class 5. Computational Chemistry Structure of molecules and their reactivities Two major areas –molecular mechanics –electronic structure.
Glycogen Phosphorylase Inhibitors: A Free Energy Perturbation Analysis of Glucopyranose Spirohydantoin Analogues G. Archontis, K. A. Watson, Q. Xie, G.

Glycogen Phosphorylase Inhibitors: A Free Energy Perturbation Analysis of Glucopyranose Spirohydantoin Analogues G. Archontis, K. A. Watson, Q. Xie, G.
Summary Molecular surfaces QM properties presented on surface Compound screening Pattern matching on surfaces Martin Swain Critical features Dave Whitley.

Summary Molecular surfaces QM properties presented on surface Compound screening Pattern matching on surfaces Martin Swain Critical features Dave Whitley.
Enhancing the C-48 STAT3 Inhibitor

Enhancing the C-48 STAT3 Inhibitor
Week 5 MD simulations of protein-ligand interactions Lecture 9: Fundamental problems in description of ligand binding to proteins: i) determination of.

Week 5 MD simulations of protein-ligand interactions Lecture 9: Fundamental problems in description of ligand binding to proteins: i) determination of.
Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid (Y. Li, Z. Zhou, and C. B. Post) Richard S. L. Stein CS 379a.

Dissociation of an antiviral compound from the internal pocket of human rhinovirus 14 capsid (Y. Li, Z. Zhou, and C. B. Post) Richard S. L. Stein CS 379a.
CHEMISTRY ANALYTICAL CHEMISTRY Fall

CHEMISTRY ANALYTICAL CHEMISTRY Fall
Inverse Kinematics for Molecular World Sadia Malik April 18, 2002 CS 395T U.T. Austin.

Inverse Kinematics for Molecular World Sadia Malik April 18, 2002 CS 395T U.T. Austin.
STUDY OF STRUCTURAL FEATURES OF PROTEINS OF BIOTECHNOLOGICAL INTEREST BY MD SIMULATIONS Anna Marabotti Dept. Chemistry and Biology, University of Salerno,

STUDY OF STRUCTURAL FEATURES OF PROTEINS OF BIOTECHNOLOGICAL INTEREST BY MD SIMULATIONS Anna Marabotti Dept. Chemistry and Biology, University of Salerno,
RNA Secondary Structure Prediction Spring 2010. Objectives  Can we predict the structure of an RNA?  Can we predict the structure of a protein?

RNA Secondary Structure Prediction Spring Objectives  Can we predict the structure of an RNA?  Can we predict the structure of a protein?
Theory of walking Locomotion on ground can be realized with three different basic mechanisms: slide lever wheel or track First two are walking mechanisms.

Theory of walking Locomotion on ground can be realized with three different basic mechanisms: slide lever wheel or track First two are walking mechanisms.
Molecular Dynamics Simulation

Molecular Dynamics Simulation
Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition?

Combination of Scattering Experiments with Molecular Simulation What Drives the Protein Dynamical Transition? Simplified Description of the Transition?

Similar presentations

Ads by Google