Important Interaction in Drug Receptor Complex And Intro to De Novo Drug Design.pptx

Vision: To Pursue Excellence in Pharmaceutical Education & Research to Develop Competent Professionals
Presented by
Yogesh Kailas Chaudhari
M. Pharm Sem II
Credit Seminar 2023-24
Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule
Topic: Important Interaction (Forces) Involved In Drug
Receptor Complex and Introduction to De Novo Drug Design
Guided by
Dr. Pawan Kumar Gupta
(Associate Professor)
Department of Pharmaceutical Chemistry

What is Drug Receptor Complex?
The term drug receptor or drug target denotes the cellular macromolecule
or macromolecular complex with which the drug interacts to elicit a cellular
response, i.e., a change in cell function.
D + R D-R Drug Response

The structure of the 20 primary amino acids are given in figure. Amino acid are
divided into hydrophobic and hydrophilic residues.

Important interaction (forces) involved in drug receptor
complex.
Interactions involved in the drug-receptor complex are the same forces
experienced by all interacting organic molecules.
I. Covalent bonding,
II. ionic (electrostatic) interactions,
III. ion-dipole and dipole-dipole
interactions,
I. Hydrogen bonding,
II. Charge-transfer interactions,
III. Hydrophobic interactions,
IV. Halogen bonding,
V. Vander Waals interactions.
These include:-

1. Covalent Bonds –
• Majority of the drug combine with their receptor by weak molecular
interaction.
• These interaction forms a strong link between the drug and it’s receptor but
individually the interaction are irreversible.
• It formed by a drug-receptor interaction, with enzymes and DNA.
Example :
The diuretics drug ethacrynic acid is an A,B-Unsaturated ketone, act by covalent
bond formation with sulfhydryl groups of ion transport system in the renal
tubules.
Ethacrynic Acid

For covalent bond formation, there should be two
poles; the electrophile and the nucleophile.
Nucleophiles in biology have the following functional groups:
 Thiol in the amino acid cysteine.
 Hydroxyl in the amino acid serine.
 Amine in the amino acid lysine.
 Carboxylate in the amino acid glutamic acid
Electrophiles
 Epoxide ring.
 Alkyl group attached to halogen.
 Positively charged centre.

2. Ionic (or Electrostatic) Interactions
• Drug and receptor groups will be mutually attracted provided they have
opposite charges. This ionic interaction can be effective at distances farther
than those required for other types of interactions, and they can persist longer.
• Basic groups such as the amino side chains of arginine, lysine are protonated
and, therefore, provide a cationic environment.
• Acidic groups, such as the carboxylic acid side chains of aspartic acid and
glutamic acid, are deprotonated to give anionic groups.
Arginine

3. Ion-Dipole and Dipole-Dipole Interactions
• Greater electronegativity of atoms such as oxygen, nitrogen, sulphur, and halogens
relative to that of carbon, will have an asymmetric distribution of electrons; this
produces electronic dipoles.
• These dipoles in a drug molecule can be attracted by ions (ion-dipole interaction) or
by other dipoles (dipole-dipole interaction) in the receptor, provided charges of
opposite sign are properly aligned.
• Dipole-Dipole interaction > ion-dipole interaction.

4. Hydrogen Bonds
• Hydrogen bonds are a type of dipole-dipole interaction formed
between the proton of a group X-H, where X is an electronegative
atom, and one or more other electronegative atoms (Y) containing a
pair of non-bonded electrons.
• X removes electron density from the hydrogen so it has a partial
positive charge, which is strongly attracted to
the non-bonded electrons of Y.
• The interaction is denoted as a dotted line,
-X-H---Y-.

5. Charge-Transfer Complexes
When a molecule that is a good electron donor comes into contact with a
molecule that is a good electron acceptor, the donor may transfer some of its
charge to the acceptor. This forms a charge-transfer complex.

6.Halogen Bonding
Covalently bonded halogen atom can act as an electron acceptor (Lewis acid) to
undergo halogen bonding with an electron-rich donor atom, such as O, N, or S. The
strength of these interactions is in
the order H=I>Br>Cl>>F.

7. Vander Waals or London Dispersion Forces
 Atoms in nonpolar molecules may have a temporary non- symmetrical
distribution of electron density, which results in the generation of a temporary
dipole.
 Consequently, intermolecular attractions, known as van der Waals forces, result.

De Novo Drug Design
De novo means start a fresh, from the beginning from the scratch.
3D structure of receptor used to design newer molecules.
It involves structural determination of the lead target complex and lead
modification using molecular modelling tools.
Ligand optimization can be done by analysing protein active site properties that
could be probable area of contact by the ligand.
Structure of the binding site can be identified from x-ray crystallography study
of the target protein containing ligand or inhibitor.
 The analysed active site properties are described to negative image of the
protein such as: Hydrogen bond donor, Hydrogen bond acceptor, Hydrophobic
contact region.

Principle
 In de novo design, the structure of the target should be known to a high resolution
and the binding to site must be well defined.
 This should define not only a shape constrain(refers to the specific 3D structure or
conformation that the receptor protein must adopt in order to properly bind to its
ligand (molecule that binds to the receptor) but hypothetical interaction sites,
typically consisting of hydrogen bonds, electrostatic and other non-covalent
interactions.
 Firstly it assembles all possible compounds and evaluating their quality which is
enable searching the sample space for novel structures with drug like properties.

• The first type of method has been described as outside in method in which the
binding site is first analyzed to determine where specific functional groups might
bind tightly.
• These groups are connected together to give molecular skeletons, which are then
converted into 'real' molecules.
• In the inside out method molecules are grown within the binding site, under the
control of an appropriate search algorithm on the basis of energy function.
• In this study flexible molecules are better than rigid molecules.
Fig. De Novo Drug Design
Two basics types of de novo design algorithms :

Types Of De Novo Drug Design
Manual Design
• It is slow.
• A single novel structure.
Automated Design
• It is much faster.
• Large number diverse structures.
Procedure For De novo Drug Design:-
1. Crystallize target protein with Bound ligand (enzyme+ ligand).
2. Acquire Structure By X-ray crystallography.
3. Identify Blinding site.

4. Identify potential binding region in the Binding site.
5. Design a lead compound to interact with the Binding site.
6. Synthesis the lead compound and test it for activity.
7. crystallize the lead compound with target protein and Identify the
actual Binding Interaction.

Important Points To Take Consideration In De Novo Drug
Design.
• Flexible molecule are better than rigid molecule because the earlier have
more likely to find the alternative binding conformation should they fail to
bind as expected. If the rigid molecule fails to bind as predicted, it may not
bind to all.
• It is pointless designing molecule which are difficult or impossible to
synthesize.
• Similarly it is pointless designing molecules which need to adopt an unstable
conformation in order to bind.

Software used in De novo drug design

Several computer software program have been which are
automatically design novel structure to fit known binding sites.
The following are some examples.
LUDI – One of the best known de novo software program is called
LUDI. Which works by fitting molecular fragments to different
regions of the binding site, then linking the fragments together.

Interaction Site
For ex - binding site contain methyl group. Program will identify the carbon of
that group as an aliphatic carbon capable of taking part in Vander Waal
interaction.
Identification of Interaction Sites
Fitting Molecular Fragments
Typically 5-30 atoms in size
Fragment bridging
Synthesis the lead compound
Other software – SPROUT , LEGAND.

APPLICATIONS
 Design of HIV 1 protease inhibitors
 Design of bradykinin receptor antagonist
 Catechol ortho methyl transferase inhibitor
Ex.entacapone and nitecapone
 Estrogen receptor antagonist
 Purine nucleoside phosphorylase inhibitors

References:
1. Wang M, Wang Z, Sun H, Wang J, Shen C, Weng G, Chai X, Li H, Cao D, Hou T. Deep
learning approaches for de novo drug design: An overview. Current opinion in
structural biology. 2022 Feb 1;72:135-44.
2. Medina JR, Blackledge CW, Heerding DA, Campobasso N, Ward P, Briand J, Wright L,
Axten JM. Aminoindazole PDK1 inhibitors: a case study in fragment-based drug
discovery. ACS medicinal chemistry letters. 2010 Nov 11;1(8):439-42.
3. Schneider G, Fechner U. Computer-based de novo design of drug-like molecules.
Nature Reviews Drug Discovery. 2005 Aug 1;4(8):649-63.
4. Silverman RB, Holladay MW. The organic chemistry of drug design and drug action.
Academic press; 2014 Mar 29.

Important Interaction in Drug Receptor Complex And Intro to De Novo Drug Design.pptx

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