Assignment on molecular recognition

1. ASSIGNMENT
PAPER CODE: DBI-CC-105B
PHARMACO AND CHEMINFOMATICS
MOLECULAR RECOGNITION AND
DOCKING
SUBMITTED TO: SUBMITTED BY:
DR. SUSHIL KASHAW RAJENDRA K RAWAT

2. Molecular Recognition
host and guest chemistry

3. Molecular recognition is the specific interaction between two or more molecules, which are
complementary in their geometric and electronic features (like two fitting pieces of a jigsaw
puzzle).
It is the specific interaction between two or more molecules through noncovalent bonding such as
hydrogen bonding, metal coordination, hydrophobic forces, van deer waals for ces, pi-pi
interactions, electrostatic and/or electromagnetic effects. Such process are crucial in biological
systems, and much modern chemical research.
The classical lock and key principle describes the interaction of compounds due to their shape and
rigidity (preorganization).
Molecular recognistion may be inter and interamolecular phenomena, is also encompasses the
“host-guest chemistry”, “supramolecular chemistry”, and “self assembly”.

4. Interaction Strength (kJ mol−1)
Covalent Bond 200–400
Ion-Ion 100–360
Ion-Dipole 50–200
Dipole-Dipole 5–50
Hydrogen Bonding 4–120
Cation-π 5–80
π–π 0–50
van der Waals < 5 (variable depending on surface
area)
Hydrophobic Related to solvent-solvent
interaction energy
Table 1. Supramolecular interaction classified under various categories

6. Types of Molecular Recognition:
Molecular recognition can be sub divided into-
1.Static molecular recognition
2.Dynamic molecular recognition.
Static molecular recognition
• It is interaction between a key and a key hole.
• It is a1:1 type complexation reaction between a host molecule and a guest molecule to form a
host-guest complex.
• To achieve advanced static molecular recognition, it is necessary to make recognition sites that
are specific for guest molecules.

7. Dynamic Recognitions:
In dynamic recognition binding the first guest at the first binding site.
Induces a conformation change that affects the association constant of the second guest at the
second binding site.
A positive allosteric site - In the case of dynamic molecular recognition the binding of the
first guest to the first binding site of a host affects the association constant of a second guest
with a second binding site

8. In the case of positive allosteric systems the binding of the first guest increases the association
constant of the second guest.
Negative allosteric systems the binding of the first guest decreases the association constant with
the second.
The dynamic nature of this type of molecular recognition is particularly important since it provides
a mechanism to regulate binding in biological systems.
Dynamic molecular recognition is also being studied for application in highly functional chemical
sensors and molecular devices.

9. Molecular Recognition in Supramolecular Systems
• Chemists have demonstrated that artificial supramolecular systems can be designed that
exhibit molecular recognition.
• One of the earliest examples of such a system is crown ethers which are capable
of selectively binding specific cations. However, a number of artificial systems have
since been established.

11. MACROCYCLIC POLYETHERS: DIBENZO-18-CROWN-6 POLYETHER AND DICYCLOHEXYL-18-
CROWN-6 POLYETHER
Submitted by Charles J. Pedersen, Checked by Edith Feng and Herbert O. House.

12. Synthetic scheme for the synthesis of crown ether based dialdehyde

13. • Molecular recognition acts as- Sensor, Molecular motor, Enzyme mimetic catalysis, Self
organization
• Binding of the guest leads to measurable change in the physical properties of the host.
• Molecular recognition is used to differentiate between enantiomers.
• Molecular recognitions in biological system-
– A non-covalent interaction between different sets of macromolecules leads to supramolecular
assemblies that serve specific sub-cellular functions in biology
– E.g. ribosomes are supramolecular assemblies of proteins & RNA., proteins, nucleic acids,
lipids,
– Cell organells-nucleus, mitochondria, endoplasmic reticulum
– Protein embedded in the lipid bilayer membrane
• An important example of molecular recognition is the antibiotic vancomycin that selectively
binds with the peptides with terminal D-alanyl-D-alaninein bacterial cells through five
hydrogen bonds. The vancomycin is lethal to the bacteria since once it has bound to these
particular peptides they are unable to be used to construct the bacteria’s cell wall.
Applications of Molecular Recognition

14. Drug properties have always been a prominent component of the development phase,
after discovery, during which detailed studies are performed on formulation, stability,
pharmacokinetics (PK), metabolism, and toxicity.
• Drug-like properties confer good ADME/Tox characteristics to a compound.
• Medicinal chemists control properties through structure modification.
• Biologists use properties to optimize bioassays and interpret biological experiments.

15. Drug-like properties are intrinsic properties of the molecules and it is the responsibility of
the medicinal chemists to optimize not only the pharmacological properties but also the
drug-like properties of these molecules
Advantages of Good Drug-like Properties
• Structural properties determine in vivo pharmacokinetics and toxicity.
• Inefficient research, attrition, and costs are reduced if compounds have good properties.
• ADME/Tox property assessment and optimization are important aspects of drug
discovery.
• Optimal clinical candidates have a balance of activity and properties.

16. Compound structure determines the fundamental properties that determine physicochemical and
biochemical properties, which ultimately determine pharmacokinetics and toxicity

17. Rules for Rapid Property Profiling from Structure
 Lipinski and Veber rules are guidelines for structural properties of
drug-like compounds.
 Rules are effective and efficient means of rapidly assessing
structural properties.

18. Lipinski Rules
 The rules are easy, fast, and have no cost to use.
 The “5” mnemonic makes the rules easy to remember.
 The rules are intuitively evident to medicinal chemists.
 The rules are a widely used standard benchmark.
 The rules are based on solid research, documentation, and rationale. The
rules work effectively.

19. Poor absorption or permeation are more likely when a molecule consist:
 >5 H-bond donors (expressed as the sum of all OHs and NHs)
 MW > 500
 logP > 5 (or MlogP > 4.15)
 >10 H-bond acceptors (expressed as the sum of all Ns and Os)
 Substrates for biological transporters are exceptions to the rule

20. Functional group H-bond donor H-bond acceptors
Hydroxyl 1 (OH) 1 (O)
Carboxylic acid 1 (OH) 2 (2 Os)
C(O)-N-R2 0 2 (N, O)
–Primary amine 2 (NH2) 1 (N)
Secondary amine 1 (NH) 1 (N)
Aldehyde 0 1 (O)
Ester 0 2 (O)
Ether 0 1 (O)
Nitrile 0 1 (N)
Pyridine 0 1 (N)
TABLE: Examples of Counting Hydrogen Bonds for Lipinski Rules

21. Veber Rules
They studied structural properties that increase oral bioavailability in rats.
They concluded that molecular flexibility, polar surface area (PSA), and hydrogen bond
count are important determinants of oral bioavailability.
Rotatable bonds can be counted manually or using software.
PSA is calculated using software and is closely related to hydrogen bonding.
Veber rules for good oral bioavailability in rats are as follows:
≤10 rotatable bonds
≤140 Å2 PSA, or ≤12 total hydrogen bonds (acceptors plus donors)

22. Application of Rules for Compound Assessment
Anticipating the drug-like properties of potential compounds when planning synthesis
Using the drug-like properties of “hits” from HTS as one of the selection criteria
Evaluating the drug-like properties of compounds being considered for purchase from a
compound vendor

23. structure-based drug design
• Structure based drug design exploits the 3D structure of target or a
pharmacophore.
- Find a molecule which be expected to interact with the receptor.
-Design entirely a new molecule from “SCRATCH” (de novo
drug/ligand design)

24. Structure-based drug design

25. Structure-based drug design

32. Molecular modeling and drug designing software:
Dock, Autodock, HyperChem, CDS etc

33. Basics of Cheminformatics
Cheminformatics refers to use of physical
chemistry theory with computer and information
science techniques.
Cheminformatics encompasses the design, creation,
organization, management, retrieval, analysis,
dissemination, visualization, and use of chemical
information.

42. Tools Used for cheminformatics
The development of software and tools for computer assisted organic synthesis are under vast
development. Some of the tools are listed below-
ISIS-Draw is a chemical structure drawing program for Windows, published by MDL
Information Systems. It is the interfacial software to ISIS/Base database.
ChemDraw is a molecule editor developed by the cheminformatics company
CambridgeSoft. ChemDraw is, along with Chem3D and ChemFinder, part of the
ChemOffice suite of programs and is available for Macintosh and Microsoft Windows.
ChemWindow, is a chemical structure drawing program with several template. The
template can be created by the customer can be saved in template folder and opened in
preference dialogue box.

43. ChemSketch, is a chemical structure drawing program with predefined templates are available for
drawing and it is more powerful and user friendly tool for structure analysis.
ChemReader is a software developer toolkit for translating digital raster images of chemical
structures into standard, chemical file formats that can be searched and analyzed with other open
source or commercial cheminformatic software.
JME Molecular Editor is a Java applet which allows to draw / edit molecules and reactions
(including generation of substructure queries) and to depict molecules directly within an HTML
page .
LogCHEM, an Inductive Logic Programming (ILP) based tool for discriminative interactive
mining of chemical fragments.
PLSR (PLS-Regression), a simple chemmetrics tool, which relates two matrix X and Y through
linear multivariate model and has the ability to analyse data with many, noisy, collinear, and even
incomplete variables in both X and Y.

44. Wendi (Web Engine for Nonobvious Drug Information), a web based integrative data mining
tool. It attempts to find non-obvious relationships between a query compound and scholarly
publications, biological properties, genes and diseases using multiple information sources [26].
ChemMine tool is an online service for small molecule analysis. It provides an interface between
cheminformatics and data mining tools for various analytical analyses in chemical genomics and
drug discovery [27].
CML (Chemical Markup Language) is degined as combination of semantic text and nontextual
information of chemical strucutre on the internet. It acts like HTML pages [39][40].
MyChemise (My Chemical Structure Editor) is a new 2D structure editor. It is designed as a Java
applet that enables the direct creation of structures in the Internet using a web browser.
MyChemise saves files in a digital format (.cse) and the import and export of .mol files using the
appropriate connection tables is also possible [41].
PubChem is an open repository for small molecules and their experimental biological activity. It
integrates and provides search, retrieval, visualization, analysis, and programmatic access tools
in an effort to maximize the utility of contributed information

45. Open Babel is a chemical tool box which interconverts chemical structures between different
formats, over 110 formats .
AmberTools is used Biomolecular simulation and analysis of polymers, nucleotides, and
synthetic organic structures.
Some other tools such as, CAS Draw, DIVA (Diverse Information, Visualization and Analysis),
Structure Checker Accord, DS Accord Chemistry Cartridge, MarvinSketch PowerMV,
TINKER, APBS, ArgusLab, Babel, ioSolveIT, ChemTK, Chimera, CLIFF, Dragon, gOpenMol,
Grace, JOELib, Jmol, IA_LOGP, Lammps, MIPSIM, Mol2Mol, AMSOL, MOLCAS, Molexel,
ICM-Pro, ORTEP, Packmol, Polar, XLOGP,PREMIER Biosoft, Q-chem, ALOGPS, Qmol,
SageMD, ChemTK Lite, Transient, CLOGP,TURBOMOLE, UNIVIS, VMD, WHATIF,
GCluto, COSMOlogic, KOWWIN are also used for similar kind of applications mentioned
above

46. Modeling of small molecules