NEW DRUG DESIGN
  • Intro
  • Solution
  • Method
  • Team
Drug Design Methodologies
Computational Solutions for Structure Based Drug Design


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The fundamental problem in computational drug design is accurately estimating ligand-receptor binding affinity. Historically, this shortcoming combined with the complexity, resources, and time requirements has hampered the utility of structure-based drug design.
However, Moore's Law coupled with recent advances in GPU driven computing have made it possible to achieve accurate results in reasonable time frames.
  • Ligand receptor binding
  • Structure-based drug design
  • Moore's Law and GPU computing
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These calculations are performed alchemically using molecular dynamics to adequately sample a suitable thermodynamic path and intermediate states.

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The measured energies during alchemical transformation are then used to computationally estimate ligand-receptor binding affinity by a number of published techniques - including:

  • Thermodynamic integration
  • Weighted Histogram Analysis Method
  • Bennett Acceptance Ratio
  • Linear Interaction Energy

Links:
  • Free Energy Calculations
  • Molecular Dynamics
  • Thermodynamic Paths and Intermediate States
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Regardless of the method employed, the accuracy of the force field used in computing the molecular energies dictates success or failure.
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Published force fields are generally accurate for proteins as there are a limited number of residues. Over a century of data has gone into their parameterization.

However, the chemical breadth and diversity of drug-like small molecules is immense, and current force fields lack the transferability to cope. This greatly compromises the accuracy of present methods.

Links:
  • Molecular modeling
  • Molecular mechanics
  • Force Field and Parameterization
Solution
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  • Solution
  • Method
  • Team