COMPUTER AIDED DRUG DESIGNMolecular Docking

3D- QSAR

Presented by…..

0Hafiz Hammad0Hassan Ali0Haroon Mir0Husham Ali0Ali Ahsan

Drug design and drug discovery

0Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target.

How drugs are discovered?

0Mainly by accident

0 Can be discovered by………..

0 screening of new drugs0 modification for improvement-by modifying existing

drugs0 mechanistic based drug design0 combining techniques- by combining different drugs

Introduction to CADD

0CADD stands for Computer Aided drug design0 lies In the hand of computational scientists, who are

able to manipulate molecule on the screen0 Rather it is a complex process involving many

scientist from various stream working together.

CONT….

0Drug design with the help of computers using:0Molecular docking0  virtual screening (structure- or ligand-based design)0QSAR

Role of CADD

0The target of Computer Assisted Drug Design (CADD) is not to find the ideal drug but to identify and optimize lead compounds and save some experiments

0The parameters expected from a drug are…….0Safety0Efficiency0Stability 0Solubility

What is Molecular Docking?

0To place a ligand (small molecule) into the binding site of a receptor in the manners appropriate for optimal interactions with a receptor.

More serious definition…..

0 It predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex.

“Docking is a term used for computational schemes that attempt to find the “best” matching between two molecules a receptor and a ligand”

LOCK AND KEY

0 Finding the correct relative orientation of the “key” which will open up the “lock”.

0 On the surface of the lock is the key hole…

0 In which direction to turn the key after it is inserted.

0 The protein can be thought of as the “lock” and the ligand can be thought of as a “key”.

Docking can be between….

0Protein - Ligand

0Protein – Protein

0Protein – Nucleotide

Basic principle

Docking involves two separate molecules.0 It initiates from folded protein chains and ligand

conformations. 0 In contrast, protein folding initiates from some non-

native protein conformations. Hence, docking is often viewed as distinct from folding.

Three Components of Docking

• Representation of the (system) receptor binding site and ligand Pre-docking

• Conformational space search of the ligand-receptor complexDuring

docking

• Evaluation of ligand-receptor interactions

During docking and

scoring

Types of Docking

0Rigid Docking (Protein- Protein Docking)  It relates to the molecules as rigid objects that cannot change their spatial shape during the docking process.

0Flexible (soft) Docking (Protein – Ligand Studies)

Docking procedures that consider possible conformational changes are termed flexible docking

Mechanics of docking

Why We Do Docking?

0To Reduce cost of formulating new drug0Structure based drug design (SBDD) for lead

generation and optimization.

Problems of Docking studies0 Protein-Protein Docking

0 This problem involves two proteins that are approximately the same size.

0 Both molecules are rigid0 Interaction produces no change in conformation0 Similar to lock-and key model

0 Protein-Ligand Docking0 Ligand is flexible but the receptor protein is rigid.0 Interaction produces conformational changes in ligand

Why is docking important?

0 It is the key to rational drug design: The results of docking can be used to find inhibitors for specific target proteins and thus to design new drugs.

0 In addition to new drug discovery, it is of extreme relevance in cellular biology

Factors affecting docking

Intramolecular forces. . . . 0 bond length0 bond angle0 dihedral angle

Intermolecular forces. . . .0 electrostatic0 dipolar0 H-bonding0 hydrophobicity0 Vander waals forces

APPLICATIONS OF MOLECULAR DOCKING

Virtual screening (hit identification) 0 docking with a scoring function can be used to

quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest.

Bioremediation Protein ligand docking can also be used to predict

pollutants that can be degraded by enzymes.

0To study the geometry of a particular complex.(Rational Design Of Drugs)

0 Identification of the ligand’s correct binding geometry in the binding site

0Prediction of the binding affinity0For predicting protein-protein interaction

Softwares0 SANJEEVINI – IIT Delhi (www.scfbio-iitd.res.in/sanjeevini/sanjeevini.jsp)

0 GOLD – University of Cambridge ,UK (www.ccdc.cam.ac.uk/Solutions/GoldSuite/Pages/GOLD.aspx)

0 AUTODOCK - Scripps Research Institute,USA (autodock.scripps.edu/)

0 GemDock(Generic Evolutionary Method for Molecular Docking) - A tool, developed by Jinn-Moon Yang, a professor of the Institute of Bioinformatics, National Chiao Tung University, Taiwan (gemdock.life.nctu.edu.tw/dock/)

0 Hex Protein Docking -  University of Aberdeen, UK (hex.loria.fr/)

0 GRAMM  (Global Range Molecular Matching) Protein docking  - A Center for Bioinformatics, University of Kansas, USA (www.bioinformatics.ku.edu/files/vakser/gramm/)

QSAR

0Quantitative structure-activity relationships (QSAR) have been applied for decades in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities.

Principle

0The difference in structural properties is responsible for the variations in biological activities of the compounds

Hansch analysis

0 In Hansch analysis, physicochemical properties are correlated with biological activity values.

0affinities of ligands to their binding sites, 0 inhibition constants,0 rate constants, and 0other biological end points, 0with atomic, group or molecular properties such as

lipophilicity, polarizability, electronic and steric properties.

Free Wilson analysis

0The Free Wilson model is a simple and efficient method for the quantitative description of structure activity relationships. It is the only numerical method which directly relates structural features with biological properties

Limitations of QSAR

0This approach has only a limited utility for designing a new molecule due to the lack of consideration of the 3D structure of the molecules.

Why 3D QSAR?

03D-QSAR has emerged as a natural extension to the classical Hansch and Free-Wilson approaches, which exploits the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques. It has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals.

3 D QSAR

0 In 3 D QSAR, 3D properties of a molecule are considered.

03D-QSAR involve the analysis of the quantitative relationship between the biological activity of a set of compounds and their three-dimensional properties using statistical correlation methods.

03 D QSAR revolves around the important features of a molecule, its overall size and shape, and its electronic properties.

3D QSAR

0Although the trial and error factor involved in the development of a new drug cannot be ignored completely, QSAR certainly decreases the number of compounds to be synthesized by facilitating the selection of the most promising candidates. Several success stories of QSAR have attracted the medicinal chemists to investigate the relationships of structural properties with biological activity.

3D QSAR -APPROACHES

0ACTIVE SITE INTERACTION –how active site interact with different molecule

0COMPARITIVE MOLECULAR FIELD ANALYSIS (CoMFA)-new approach to structure/ activity correlation.

0Representation of ligand molecule by their steric and electrostatic field.

3D QSAR- ADVANTAGES

0  Useful in the design of new drugs.0 The necessary software and hardware are readily

affordable and relatively easy to use. 0 Favorable and unfavorable interaction are represented

by 3 D contours around a representative molecule. 0 Graphical representation of beneficial and non

beneficial interactions help to define a new structure.0 In 3 D QSAR, the properties of test molecule are

calculated individually by computer program.

3D-QSAR Assumptions

The effect is produced by modeled compound and not it’s metabolites.The binding site is the same for all modeled compounds.The biological activity is largely explained by enthalpic processes.The system is considered to be at equilibrium, and kinetics aspects are usually not considered.

Advantages over QSAR

0No reliance on experimental values

0Not restricted to molecules of same structural class

0Predictive capability