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DNA Technology in the New Millennium

DNA Technology in the New Millennium. Molecular Modeling and Drug Discovery Techniques Summer 2002 Dr. Joseph Smith Science Department Cabrini College. Today’s Session. review some background on computational methods examples of some simple calculations on a small molecule

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DNA Technology in the New Millennium

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  1. DNA Technology in the New Millennium Molecular Modeling and Drug Discovery Techniques Summer 2002 Dr. Joseph Smith Science Department Cabrini College

  2. Today’s Session • review some background on computational methods • examples of some simple calculations on a small molecule • examples of some simple calculations on peptides and nucleic acids

  3. Spartan Software Developed by Wavefunction, Inc. 18401 Von Karmon, Suite 370 Irvine, CA 92612 www.wavefun.com sales@wavefun.com

  4. Value of Computational Techniques in Drug Discovery • allows prediction and understanding of molecular properties and chemical behavior • allows understanding of structure–activity relationships (SARs) • allows insight into potential drug candidates

  5. Computerized Calculations • power of contemporary chips allows for high speed calculations on molecules in a reasonable amount of time • graphical user interface allows for easy construction of molecules and convenient visualization of molecular properties such as: -molecular structure -electric dipole moment -charge distribution -highest occupied molecular orbitals (HOMOs) -lowest unoccupied molecular orbitals (LUMOs) -electron density maps

  6. Types of Calculations I) Methods based on Classical Mechanics (aka molecular mechanics or force field methods) • ex. MMFF, SYBYL, MM2, MM3 • simple and fast • treats a molecule as a collection of balls (atoms) and springs (bonds) • good for small and large molecules

  7. Types of Calculations II) Methods based on Quantum Mechanics • three theoretical models 1) semi-empirical, ex. AM1, PM3, MNDO 2) ab initio, ex. Hartree-Fock, MP2, MCSCF 3) density functional theory, ex. SVWN, BP • all three models are used to approximate solution to Schrodinger equation HY=EY • complex and require longer calculation times • restricted to small molecules

  8. Molecular Mechanics Calculations Minimizes energy of molecule relative to strain energy associated with: 1) bond length 2) bond angle 3) torsion angle 4) van der Waals interactions 5) electrostatic interactions 6) other interactions depending on method

  9. Molecular Mechanics Calculations • For a given structure, energy minimization explores potential energy surface and results in lowest energy conformation (local energy minimum) • The resulting optimized geometry manifests the least strain possible (bond, angle, torsion, van der Waals, electroctatic, etc.) • A different calculation (ex. Monte Carlo simulation) is required to guarantee that local minimum is also the global minimum

  10. Approach Used in Molecular Modeling 1) identify problem 2) build molecule 3) run calculation (energy minimization) 4) interpret results

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