BY

NEERAJ KANT SHARMA TEERTHANKER MAHAVEER UNIVERSITY, MORADABAD, INDIA

Specialized discipline for design of new molecule or an existing drug with improved activity with the help of computer generated results. Use of various structural features to identify the nature of the molecule. Identification of structure of receptor and its interaction with the ligand. Design of various possible models for calculation of most suitable conformer.

Different bioinformatics tools. Molecular docking QSAR

Docking attempts to find the best matching between two molecules

Given two biological molecules determine:

- Whether the two molecules interact

the interaction while minimizing the total energy of the complex Goal: To be able to search a database of molecular structures and retrieve all molecules that can interact with the query structure

- If so, what is the orientation that maximizes

It is of extreme relevance in cellular biology, where function is accomplished by proteins interacting with themselves and with other molecular components 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. It is gaining importance as the number of proteins whose structure is known increases

Example: HIV-1 Protease

Active Site (Aspartyl groups)

Both molecules are flexible and may alter each others structure as they interact:
Hundreds to thousands of degrees of freedom (DOF) Total possible conformations are astronomical

Identification of structure of the receptor Drawing the 2D structure Conversion of 2D structure to 3D Calculation of energy and energy minimization Conformational search Superimposition of ligands to check flexibility Docking of low energy conformer with receptor

May be identified by various literatures Structure may be obtained form PDB Study of the nature of the receptor Finding the binding site for ligand

Crystal structure of tyrosine kinase(PDB ID 1Y6A)

Drawing softwares include ACD labs Chemdraw Chem ultra Chem office QSAR+
Ball and stick model of a ligand

Low energy conformers bind more effectively to receptor Optimization and Calculation of current energy of molecule Minimization of energy

High energy conformer

low energy conformer

Performed to obtain various possible interactions and binding modes of inhibitor to the receptor Various contact between amino acid chain of receptor and ligand Possible hydrogen bonds between receptor and ligand Suggests best fit model

Good contacts

Hydrogen bonds

Surface structure

 DOCK (I. D. Kuntz, UCSF) AutoDOCK (Arthur Olson, The Scripps Research

Institute)

RosettaDOCK (Baker, Washington Univ., Gray, Johns

Hopkins Univ.) FlexX ArgusLabs Schrodinger Hex GOLD

Quantative Structure-Activity Relationships A QSAR is a mathematical relationship between a biological activity of a molecular system and its geometric and chemical characteristics. QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these rules can be used to evaluate the activity of new compounds.

Compounds + biological activity

QSAR

New compounds with improved biological activity

The number of compounds required for synthesis in order to place 10 different groups in 4 positions of benzene ring is 104

Solution: synthesize a small number of compounds and from their data derive rules to predict the biological activity of other compounds.

Input: n descriptors P1,..Pn and the value of biological activity (EC50 for example) for m compounds
Bio P1
3.7 0.4

P2

..

..

..

..

Pn

Cpd 1 Cpd2

0.7 3.2

.
Cpdm

Structural descriptors are of immense importance in every QSAR model. Common structural descriptors are pharmacophores and molecular fields. Superimposition of the molecules is necessary. 3D data has to be converted to 1D in order to use PLS.

The effect is produced by modeled compound and not its metabolites. The proposed conformation is the bioactive one. The binding site is the same for all modeled compounds. The biological activity is largely explained by enthalpic processes. Entropic terms are similar for all the compounds. The system is considered to be at equilibrium, and kinetics aspects are usually not considered. Pharmacokinetics: solvent effects, diffusion, transport are not included.

Select a set of molecules interacting with the same receptor with known activities.

Calculate features (e.g. physicalchemical properties, etc., 2D, 3D)

Divide the set to two subgroups: one for training and one for testing.

Build a model: find the relations between the activities and properties (regression problem, statistic methods, machine learning approaches, etc).
Test the model on the testing dataset.

Publish a paper if your results are good!

You can also develop new descriptors, new methodologies, algorithms, etc.

Quantifying the relationship between structure and activity provides an understanding of the effect of structure on activity. It is also possible to make predictions leading to the synthesis of novel analogues. The results can be used to help understand interactions between functional groups in the molecules of greatest activity, with those of their target

Tripos CoMFA VolSurf Catalyst Serius QSAR+ Schrodinger DISCOVER