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This slides gives you the information related to computer aided drug design and its application in drug discovery. Also you learn the Quantum mechanics related to the molecular mechanics. Theory related to molecular modeling and how the molecular modeling helps in drug discovery.

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- 1. SWAMI RAMANAND TEERTH MARATHWADA UNIVERSITY, NANDED Molecular modeling and docking Presented By Akshay Avinash Kank (M.Pharm, First Year) Guided By Proff. Dr. S.R. Butle (M.Pharm Ph.D)
- 2. Parameters • Computer Aided Drug Design • Introduction to molecular modeling • Types of molecular modeling • Quantum mechanics o Ab- initio methods o Semi-empirical methods • Application • References
- 3. Computer Aided Drug Design • CADD represents computational methods and resources that are used to facilitate the design and discovery of new therapeutic solutions. • Drug design with the help of computers may be used at any of the following stages of drug discovery – Hit identification using virtual screening. QSAR
- 4. Objective of CADD • TO CHANGE FROM : • Random screening against disease assays. • Natural products, synthetic chemicals. • CHANGE TO : • Rational drug design and testing • Speed up screening process • Efficient screening • De novo design • Integration of testing into design process
- 5. Introduction • Molecular modeling is define as Theoretical methods and computational techniques use to mimic the behavior of molecules and molecular system. • Molecular modeling helps the scientist to visualize molecule, to discover new compounds for drugs. • The common feature of molecular modeling techniques is the atomistic level description of the molecular system. • Goal : To develop a sufficient accurate model of the system so that physical experiment is not necessary.
- 6. Why medicinal chemist use models? • To help with analysis and interpretation of experimental data. • To uncover new laws and formulate new theories . • To help solve new problems and hint solutions before doing experiments • To help in design new experiments • To predicts properties and quantities that is difficult or even impossible to observe experimentally.
- 7. Introduction to molecular modeling • Molecular modeling is anything that requires the use of a computer to paint, describe or evaluate any aspect of the properties of structure of a molecule(Pensak, 1989). • Methods used in the molecular modeling arena regard automatic structure generation analysis of three dimensional(3D) databases, construction of protein models by techniques based on sequence homology, diversity analysis, docking of ligands or continuum methods.
- 8. Introduction to molecular modeling • Thus today molecular modeling is regarded as a field concerned with the use of all sort of different strategies to modes and to deduce information of a system at the atomic level. • It is possible to conclude that computational chemistry is the nucleus of molecular modeling. • Because it includes the all methodologies used in computational chemistry like computation of the energy of a molecular system, energy minimization, Monte Carlo methods or molecular dynamics.
- 9. Molecular Modeling Strategies • Direct Drug Designing • in this approach, the three dimensional features of the known receptor site are determined from X-ray crystallography to design lead molecule. • Here, receptor site geometry is known; the problem is to find a molecule that satisfies some geometry constraints is also good chemical match. • After finding good candidates according to these criteria a docking step with energy minimization can be used to predict binding strength. • Indirect drug design • The indirect drug design approach involves comparative analysis of structural features of known active and inactive molecules that are complementary with a hypothetical receptor site.
- 10. Quantum Mechanics • Quantum mechanics provides information about both nuclear position and distribution. • Based on study of arrangement and interaction of electron and nuclei of a molecular system. • It dose not require the use of parameters similar to those used in molecular mechanics. • It is based on the wave properties of electrons and all material particles. • The mathematics of wave motion applied to electrons, atomic and molecular structure.
- 11. Quantum Mechanics • Quantum mechanics based on the First Principles. • In this approach, nuclei are arranged in the space and the corresponding electron are spread all over the system in a continuous electronic density and computed by solving the Schrodinger equation.
- 12. Quantum Mechanics • For biomolecules this process can be done within the Born- oppenheimer approximation, and for most of the purposes the Hartee-Fock self consistent field is the appropriate procedure to compute the electronic density and the energy of the system.
- 13. Types Of Quantum Mechanics Ab-Initio Methods Hartree-Fock Approximation Density Functional Theory Semi-Imperical Methods
- 14. Hartree-Fock Approximation • The central field approximation means columbic electron- electron repulsion is taken into account. • The energies are calculated in units called Hartrees(1 Hartree= 27.2116 eV) • Advantages of this method is that it breaks the many electron Schrodinger equation into many simpler one electron equations. • Hartree’s method was to write a plausible approximate polyelectronic wave function for an atom as the product of one-electron wave function.
- 15. Hartree-Fock Approximation •Advantages- 1. Dose not depend on experimental data 2. Small system 3. System requiring high accuracy • Disadvantages- 1. Computationally expensive and time consuming.
- 16. Density functional Theory • Density functional theory is based not on the wave function, but rather on the electron probability density function or electron density function, commonly called simply the electron density or charge density. • These theory used a statistical model to approximate the distribution of electrons in an atom. • It is based on the sum of the exchange and correlation energies of a uniform electron gas can be calculated exactly knowing only its density.
- 17. Density functional Theory • Advantages- 1. Dose not depends on experimental data 2. Small system 3. System requiring high accuracy • Disadvantages- 1. There are difficulties in using density functional theory to properly describe intermolecular interactions, especially van der Waals forces(dispersion); charge transfer excitations; transition states, global potential energy surfaces and some other strongly correlated system.
- 18. Semi-Empirical Method • Semi-empirical quantum chemistry method is based on the Hartree-Fock formalism, but make many approximations and obtain some parameters from empirical(Experimental) data. • They are very important in computational chemistry for treating large molecules where the full Hartree-Fock method without the approximations is too expensive. • The use of empirical parameters appears to allow some inclusion of electron correlation effects into the methods.
- 19. Semi-Empirical Method • Advantages- 1. Semi-empirical calculations are very fast compared to Ab initio and even to Density functional theory 2. Medium sized systems(hundreds of atoms) • Disadvantages- 1. Dose depend on experimental data 2. Small system 3. Low accuracy
- 20. References • Practical application of computer aided drug design, By Paul S. Charifson, marcel dekker INC. • Chapter 3, molecular modeling techniques, By Swami Ramanand Teerth Marathwada University. • Basis of molecular modeling and docking, slide share • https://www.slideshare.net/ashwinimushunuri96/applications -of-molecular-modeling • https://www.slideshare.net/RikeshlalShrestha/molecular- modelling-75429338
- 21. THANK YOU

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