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DFT Presentation.pptx
- 1. National Conference onRecent Progress and Developments in Pharmaceutical Sciences DFT: Tools and Protocols for Drug Design Rajesh K. Das Department of Chemistry University of North Bengal
- 2. Parameters • Computer AidedDrug Design • Introduction to molecular modeling • Types of molecular modeling • Quantum mechanics o Ab- initio methods o Semi-empirical methods o DFT • Applications • References
- 3. Computer Aided DrugDesign usedto facilitate the design and discovery of new therapeutic drugs. used at any of the following stages of drug discovery – Hit identification using virtual screening. QSAR
- 4. Objective ofCADD • TOCHANGE 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 to molecularmodeling • 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.
- 6. Molecular ModelingStrategies • DirectDrug Designing • Designing of lead molecule. • receptor site geometry is known; • docking step with energy minimization can be used to predict binding strength. • Indirect drug design • receptor is unknown • The indirect drug design is done from the structure activity relation with a hypothetical receptor site.
- 7. Quantum Mechanics information aboutboth nuclear position and distribution. Arrangement and interaction of electron and nuclei of a molecular system. nuclei are arranged in the space the corresponding electron are spread all over the system in a continuous electronic density computed by solving the Schrodinger equation Features
- 9. Quantum Mechanics Applications • Forbiomolecules this process can be done within the Born- oppenheimer approximation • the purposes of the Hartee-Fock self consistent field is the appropriate procedure to compute the electronic density and the energy of the system
- 10.
- 11. Hartree-FockApproximation • The centralfield approximation means columbic electron-electron repulsion is taken into account. • The energies are calculated in units called Hartrees(1 Hartree= 27.2116 eV). • Polyelectronic wave function for an atom as the product of one-electron wave function.
- 12. Hartree-FockApproximation •Advantages- 1. Small system 2.System requiring high accuracy • Disadvantages- 1. Computationally expensive 2. time consuming.
- 13. Semi-Empirical Method • Semi-empiricalquantum chemistry method is based on the Hartree-Fock formalism, but make many approximations. • They are very important in computational chemistry for treating large molecules where the full Hartree- Fock method without the approximations is too expensive. .
- 14. Semi-Empirical Method • Advantages- Semi-empirical calculations are very fast compared to Ab initio and even to Density functional theory Medium sized systems(hundreds of atoms) • Disadvantages- Low accuracy
- 15. Density functionalTheory • Advantages- Small system High accuracy • Disadvantages- Difficulties to describe intermolecular interactions, especially vander Waals forces, charge transfer excitations; transition states, global potential energy surfaces and some other strongly correlated system
- 16. STO : SlaterType Orbital GTO: Gaussian Type Orbital CGTO: Contracted Gaussian Type Orbital BASIS SET: A basis set in theoretical and computational chemistry is a set of basis functions which are combined in linear combinations to create molecular orbitals Basis Set Basis function Polarisatio n function Diffuse function
- 17. STO Basis SetDevelopment: STO - nG n= no. of Gaussian primitive function used to represent one STO STO-3G STO-4G STO-6G STO-3G* (polarised version of STO-3G) Pople Basis Set : X-YZg X=no. of primitive Gaussian basis funcion Y= linear combination of Y primitive Gaussian function Z= linear combination of Z primitive Gaussian function
- 18. X-YZg Double zeta basisset X-YZWg Triple zeta basis set 3-21G*-polarisation function on heavy atoms 3-21G** - polarisation function on heavy atoms + hydrogen wave function 3-21+G - Diffuse function on heavy atoms 3-21++G - Diffuse function on heavy atoms + hydrogen wave function 3-21+G* - Polarisation function on heavy atoms + hydrogen wave function + diffuse function on heavy atoms
- 19. UHF = Foropen shell molecules, uses different MOs for the different spinning of electrons. RHF = For closed shell molecules, uses same MOs twice for the different spinning of electrons. B3LYP = The exact energy function is expressed in terms of Kohn- Sham orbitals rather than the density. It is known as implicit density functional. One of the most commonly version is B3LYP (Becke, 3-parameter, Lee-Yang-Peer. RB3LYP: opposite spin in the open shell UB3LYP: unpaired spin in the open shell Restricted Unrestricted
- 21. Output Descriptors HOMO LUMO Dipole Moment GlobalReactivity Descriptors: Ionisation Potential (I)= EHOMO Electron Affinity (A) = -ELUMO Chemical Potential (µ) = (EHOMO+ELUMO)/2 Global hardness (ɳ) = (ELUMO-EHOMO)/2 Global softness (S) = 1/ɳ Electronegativity (σ) = - µ Electrophilicity index (ω) = µ2/2ɳ
- 23. Fig: Chemical Structure(A), optimized structure using DFT-RB3LYP 6-31(G) of HAM A B
- 24. Table 1: Calculatedenergy values (eV) of Hamamelitanin in different solvents using DFT-RB3LYP 6-31(G) Compou nd EHOMO (eV) ELUMO (eV) EHOMO-1 (eV) ELUMO+1 (eV) ELUMO – EHOMO (eV) ELUMO+1- EHOMO-1 (eV) Etotal (eV) Gas -155.859 -34.207 -161.708 -21.176 121.652 140.532 -49696.25 Water -159.487 -32.282 -163.263 -25.619 127.205 137.644 -49695.38 DMSO -159.265 -31.394 -160.746 -23.323 127.871 137.423 -49695.68 CHN -159.117 -28.876 -160.153 -20.954 130.241 139.199 -49695.85 The chemical reactivity of the HAM in the various solvents follows the order: Gas > Water > DMSO > Cyclohexane
- 25. Out of the34 tested compounds 10 models have the best docked as compared to the standard drug hamamelitanin.
- 29. All compounds dockedin the same domain of receptor
- 35. Higher no. of–COOH and –OH groups are responsible for good binding affinity towards M protease.
- 36.
- 42. Plants : OcimumSanctum (Tulsi), Zingiber Officinale (Ginger), Justicial Adhatoda (Vasaka)
- 43. Docking of Ligandto the Active site of Receptor
- 44. Optimized Inhibitors HOMO LUMO DM ETOTAL logP MV BBB PPB TPSA Natoms nON nOHNH nrotb CMC MDDR WDI Rule offive Drug- likeness Drug Score IC50 (µM) Molecular Docking Optimized Structure (Using MD simulation) ∆G binding (kcal/mol) Protein (PDB) Inhibitors (binding db) ADME PreADMET mol inspiration Osiris Property Explorer Functionalisation QM Best potential Drugs ?
- 45. References • Practical applicationof 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
- 46. Acknowledgement Late Prof.Dr. Asim K. Bothra, Raiganj University to motivate me to conduct research work in this field. High-Performance Computing (HPC) cluster of the University of North Bengal for the computational facility UGC, New Delhi for start- up grant
- 47.