SOFTWARE FOR QUANTUM-

PHARMACOLOGICAL INVESTIGATIONS

Reporters: Voloshin A., Nebesna T.Scientific adviser: prof. Chekman I. S.

National O.O. Bogomolets Medical University

Pharmacology and Clinical Pharmacology Department

Quantum pharmacology

- area of science covers the use of electronic structure theory to de novo design of drugs, extraction of structure activity relationships and development of pharmacophores to rationalise the drug's mechanism

– W.G. Richards, 1977.(Oxford University, England).

Purpose• To analyze the software which can be used

for quantum-chemical calculations of drugs properties.

• To calculate quantum-chemical properties of beta1-adrenoblocker Atenolol.

• To propose optimal algorithm for quantum-pharmacological investigations.

What you see is what you get

ChemOffice (left) and HyperChem (right) - enables you to create color models of chemical and biochemical compounds. Once you have a model, you can calculate a variety of molecular properties - electrostatic potentials, bond energies, and spectrum prediction, and more.

3D Molecule file formats

The most popular:• ISIS Sketch (*.skc)• MDL MolFile (*.mol)

ChemOffice, HyperChem, ChemCraft can save/open

such files.

Types of Calculations:Molecular mechanics methods

The term “molecular mechanics” refers to the use of Newtonian mechanics to model molecular systems. The potential energy of all systems in molecular mechanics is calculated using force fields.

Classical force fields• AMBER (Assisted Model Building and Energy

Refinement) – developed by Peter Kollman's group at the University of California, widely used for proteins and DNA.

• CHARMM (Chemistry at HARvard Molecular Mechanics) - developed at Harvard, used for both small molecules and macromolecules.

• GROMOS - a force field that comes as part of the GROMOS (GROningen MOlecular Simulation package), has been developed for application to aqueous or apolar solutions of proteins, nucleotides and sugars.

• MM2, MM3, MM4, MM+ - developed by Norman Allinger, parametrized for a broad range of molecules

Types of Calculations: Semi-empirical methods

1) PM3 uses two Gaussian functions for the core repulsion function, instead of the variable number used by AM1 (which uses between one and four Gaussians per element);

2) the numerical values of the parameters are different;3) the philosophy and methodology used during the parameterization: whereas

AM1 takes some of the parameter values from spectroscopical measurements, PM3 treats them as optimizable values.

Semi-empirical quantum chemistry methods are based on the Hartree-Fock formalism, but make many approximations and obtain some parameters from empirical data.

AM1 (Austin Model 1) - based on the Neglect of Differential Diatomic Overlap integral approximation. PM3 (Parameterized Model number 3) - method uses the same formalism and equations as the AM1 method. The only differences are:

Input 3D Coordinates of atomic nuclei

Initial GuessMolecular Orbitals

(1-electron vectors)

Fock MatrixFormation

Fock MatrixDiagonalization

SCFConverged?Calculate

Properties

END

YES NO

Types of Calculations:Nonempirical methods. Ab initio

The term ab initio indicates that the calculation is from first principles and that no empirical data is used.

Advantages: useful for a broad range of systems does not depend on experimental datacapable of calculating transition

states and excited states

Disadvantages: computationally expensive

Best for:  small systems (tens of atoms) systems involving electronic transitions molecules or systems without available experimental data ("new"

chemistry) systems requiring rigorous accuracy

Some common computer software installed and used at our department for medicinal chemistry includes: ChemCraft, ChemOffice, HyperChem, PC GAMESS

Types of Calculations: Comparison

Type of calculation

Method Duration of Calculation (for Atenolol molecule)

Application in quantum pharmacology

Molecular mechanics

MM+ 22 sec.

geometry optimization and calculation properties of macromolecules: proteins (enzymes, receptors), nucleic acid

Semi-empirical PM3 20 min.geometry optimization of small organic

molecules (drugs, neurotransmitters, metabolites)

Ab initio HF (6-31G) 28 h.calculation of energy parameters for

small organic molecules (drugs, neurotransmitters, metabolites)

Modern tendency: - Combine MM/QM calculations for macromolecules;- Ab initio calculations (geometry optimization and properties calculation for drugs) – HF or DFT;- Solvation of calculated molecules

Molecular Descriptors:Partial charges, dipole

moment• Electrical charges in the molecule are obviously the

driving force of electrostatic interactions. • Most modern semi-empirical methods use Mulliken

population analysis.

Molecular Descriptors. Electrostatic potential

The molecular electrostatic potential is the potential energy of a proton at a particular location near a molecule.

Negative electrostatic potential corresponds to a attraction of the proton by the concentrated electron density in the molecules (colored in green).

Positive electrostatic potential corresponds to repulsion of the proton by the atomic nuclei in regions where low electron density exists and the nuclear charge is incompletely shielded (colored in shades of violet).

Molecular Descriptors. HOMO, LUMO

The role of frontier orbitals in chemical reactions: molecules share loosely bonded electrons which occupy the frontier orbitals, that is the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO)

- K. Fukui, R. Hoffman

The first ionization energy of a molecule is equal to the energy of the highest occupied molecular orbital (the HOMO), and the electron affinity is the negative of the energy of the lowest unoccupied, i.e. virtual, orbital (the LUMO).

- Tjalling C. Koopmans

Molecular Descriptors.Ionization potential (IP), Electronic affinities (EA),

Electronegativity, Hardness, Softness, Electrophilicity index

(Electronegativity)

EA

IP

2

(Hardness) 2

EAIP

(Softness)

(Electrophilicity index)

2

1S

2

2758.6

05.5

eV

099.0S 1eV

522.4

eV

Properties Calculated value

Electronegativity

Hardness

Softness

Electrophilicity index

Protein Data BankThe Protein Data Bank (PDB) is a

repository for 3-D structural data of proteins and nucleic acids. These data, typically obtained by X-ray crystallography or NMR spectroscopy and submitted by biologists and biochemists from around the world, are released into the public domain, and can be accessed for free.

Docking algorithms

• Require 3D atomic structure for protein, and 3D structure for compound (“ligand”)

• May require initial rough positioning for the ligand

• Will use an optimization method to try and find the best rotation and translation of the ligand in the protein, for optimal binding affinity

Docking Block-Sheme

Docking programs• DOCK

– Developed in Tak Kuntz’s group at UCSF - http://www.cmpharm.ucsf.edu/kuntz/dock.html

– Shape algorithm– Recent versions allow for ligand flexibility

• GOLD– Developed at Sheffield University, distributed by CCDC

http://www.ccdc.cam.ac.uk/– Uses genetic algorithm– Flexible ligand

• FLEXX– Distributed by Tripos – http://www.tripos.com– Flexible ligand

• FRED– By OpenEye Scientific – http://www.openeye.com– Rigid, but able to use multiple, well chosen conformers– Very fast

• AUTODOCK– Scripps Lab http://www.scripps.edu/pub/olson-web/doc/autodock/– Uses Genetic Algorithm

• LIGANDFIT– Accelrys http://www.accelrys.com/cerius2/c2ligandfit.html

ConclusionsCreating of ligand molecule (2D ⃗ 3D) – Programs HyperChem,

ChemOffice

↓

Geometry optimization(in gas or aqueous media)

ММ+ (molecular mechanics)АМ1, РМ3, ZINDO (semiempirical calculations)

ab initio (non empirical calculations)Programs HyperChem, GAMESS

↓

Optimal basis: 6-31 G **(d, p)PCM – solvation model

↓

Work with macromolecule: viewing Ras.Mol, docking - AutoDock

Ab actu ad potentiamОт действительного к

возможному…