Certain basic concepts fundamental to Rational Drug Design - An Introduction

1. Some building blocks for
Rational Drug Design…

2. GENERAL SCREENING OF DRUGS
 Earlier methods of drug discovery…
• ‘Trial-and-error’ testing of chemical substances (potential
drugs) on animals or cultured cells
• Observing the ‘apparent effects’.
 General or random screening is the arbitrary screening
of large sample collections (chemical entities or
potential drugs) without any scientific rationale, to
identify potential therapeutic uses in a ‘hit-or-miss’
strategy.
 General screening has become more expensive and
time consuming because of the vast collection of
samples.

3. SERENDIPITY
 It is ‘the accidental observation of beneficial unintended
effects of a drug entity’.
 Is an important source of drug discovery (unintentional
strategy);
 Is used to produce new drugs;
 Examples:
 Discovery of Penicillin by Alexander Fleming.
 Amantidine (antiviral drug) was observed to cure some
symptoms of Parkinson’s disease.
 Sildenafil citrate (for erectile dysfunction) and Minoxidil
(prevention of hair loss) – these 2 drugs were actually
tested for CV applications and failed in those tests.
 Hallucinogenic effects of LSD (Lysergic acid diethylamide)
was accidentally discovered by Albert Hoffman. He was
actually testing LSD to treat migraines and bleeding after
childbirth.

4. RATIONAL DRUG DESIGN
 Rational drug design begins with a knowledge of
specific chemical responses in the human body (body’s
response to the potential drug) or target organism, in
order to ultimately create a treatment profile.
 As the knowledge of drugs’ molecular chemistry
increased, general drug screening was replaced by
‘Targeted screening’ which was more focussed.
 Targeted screening partially leverages the concept of
rational drug design. It involves an understanding of…
• SARs of various classes of compounds
• Mechanism(s) of interaction of the compounds with
potential target sites.

5. STEPS INVOLVED IN RATIONAL DRUG DESIGN
1) Designing the candidate compounds
2) Studying their 3D structures to determine how they
interact with a specific target (cells, receptors,
biological pathways etc….)
3) Testing of the design (testing step 2)
 Rational Drug Design is a process used in the
biopharmaceutical industry to discover and develop
new drug compounds.
 RDD uses a variety of computational methods to..
• identify novel compounds;
• design safe and efficacious compounds;
• develop compounds into clinical trial candidates;

6. TYPES OF COMPUTATIONAL METHODS
 Structure-based drug design
 Ligand-based drug design
 De Novo design and homology modelling
• The type of the drug and the drug target determines
the method to be followed.
• Drug Target: is a key molecule involved in a particular
metabolic or signaling pathway (that is specific to a
disease condition or pathology; infectivity and survival
of a pathogen).

7.  A conventional approach is to stop a pathway (in the
diseased state) by causing a key molecule to stop
functioning.
 Drug molecules are designed to bind to the active site
of the key molecule and inhibit it.
 The drug molecules should be designed in such a way
so as not to affect other important molecules which are
structurally similar to the key molecule.
 Another approach is to enhance the normal pathway
by promoting specific molecules in the normal pathway
(that may have been affected in the diseased state).

8. STRUCTURE-BASED DRUG DESIGN (SBDD)
 SBDD has increased in importance because it enhances
drug specificity.
 Even small molecules have significant ‘specific
information’ within them. Egs.: LTs, steroids,
catecholamines, nucleosides, excitatory AAs, ACh etc..
 The high degree of selectivity aids in drug design.

9. COMPUTER-ASSISTED DRUG DESIGN (CADD)
 CADD uses computational chemistry to discover,
enhance or study drugs and related biologically active
molecules.
 Methods used: simple molecular modelling, molecular
mechanics, molecular dynamics, semi-empirical
quantum chemistry methods and density functional
theory.
 The 3D structure of protein targets is most often
derived from X-ray crystallography or NMR techniques.
 These methods can resolve the structure of proteins to
a resolution of a few angstroms (about 500,000 times
smaller than the diameter of the human hair).
 This ability to work at such high resolution makes
CADD one of the most powerful methods in drug
designing.

10.  Examples of structure-based CADD….
• HIV-1 PIs, HIV entry inhibitors
• Thymidylate synthetase inhibitors
• M1selective muscarinic agonists
• Purine nucleoside phosphorylase inhibitors
• Cimetidine (H2RA)
• Dorzolamide (carbonic anhydrase inhibitor used to
treat glaucoma)
• Many of the atypical antipsychotics
• Selective COX-2 inhibitors
• SSRIs
• Probenecid
• Zolpidem (non-BZs)

11. LEAD OPTIMIZATION IN CADD
 Lead optimization is the process of refining the 3D
structures of the lead compounds.
 Researchers systematically modify the structure of the
lead compound and test how well each modification
binds to the target site.
 In drug design, the purpose of exchanging one
bioisostere for another is to enhance the desired
biological or physical properties of a compound without
making significant changes to the chemical structure.

12. DRUG DEVELOPMENT THROUGH GPCRs
 GPCRs are the largest and most important family of
drug targets.
 More than 50% of drugs currently in market are based
on GPCRs.
 GPCRs have broad range of mechanisms by which they
transduce information through various channels.
 GPCRs are initially activated through binding of
peptides, neurotransmitters, hormones, amino acids,
amines, nucleotides, nucleosides, PGs etc…
 GPCRs then activate the G proteins.
 The above step is very significant in many disorders
(CV, neurological, metabolic and cancers).
 Identification of the roles of GPCRs is still ongoing.

13. FOR YOUR INFO …

14.  Isosteres: 2 molecular fragments containing identical
numbered arrangement of electrons, and thus, possess
similar properties.
 Isosteric modification: Is the replacement of an atom or
group of atoms in a molecule, by another group with
similar electronic and steric configurations.
 Ligand: ions or neutral molecules that bond to a central
metal atom or ion.
 Bioisosteric replacement:
• A common method of lead optimization;
• Specific functional groups in a ligand are replaced
/substituted by other groups to improve the binding
characteristics of the ligand.

15. STEREOISOMERS
 The pharmacological activity of stereoisomers is a well-
documented fact.
 The highly active enantiomer takes part in a minimum
of 3 intermolecular interactions with the receptor.
 The less active enantiomer can interact with a
maximum of 2 sites only.
 The interaction between a drug and a receptor is
associated with bonding interactions between the sites
on the drug and complementary sites on the receptor.
 The 3D spatial arrangement of such sites on the drug is
very significant.
 Egs. of stereoisomers:
+ and – adrenaline
+ and – ephedrine and pseudoephedrine
+ and – dopa

16. ENZYME INHIBITORS
 Are molecules that bind to an enzyme and inhibits it’s
action.
 Inhibition of a carefully selected target enzyme(s) in a
biological pathway would lead to overall production of a
complex/compound that is crucial in the disease
state.
 Egs.:
• Allopurinol inhibits xanthine oxidase, thereby reducing the
production of uric acid from Xanthine. (xanthine oxidase
aids in the conversion of xanthine to uric acid).
• Bacteria produce β-lactamase enzyme for protection
purposes. Clavulanic acid (being an inhibitor of this
enzyme) is co-administered with Penicillin G in order to
preserve the antibacterial action of the latter. (β-
lactamase inactivates most penicillins).
• L-dopa is readily metabolized by peripheral DDC. So, it is
administered along with Carbidopa (a DDC inhibitor) in
order to reduce it’s (L-dopa) metabolism.

17.  Sequential chemotherapy involves the use of 2
inhibitors simultaneously on a ‘metabolic chain’
(sequence in a metabolic pathway) with the aim of
achieving a greater therapeutic effect than by the
usage of either drug alone.
• The best known combination is Cotrimoxazole
(Trimethoprim + Sulfamethoxazole). Sulfamethoxazole is
a dihyropteroate synthetase inhibitor and Trimethoprim is
a DHFR inhibitor.

19. GENOMICS
 Is the analysis of the function and structure of genomes
by employing various techniques (recombinant DNA,
DNA sequencing methods and bioinformatics).
 The recent advances in genomics and genomic
techniques have changed the direction of drug
discovery.
 The anticipated benefits of genomics:
• Improved diagnoses of disease(s)
• Earlier detection of a person’s genetic predisposition to
disease(s)
• Rational drug design
• Gene therapy
• Personalized and customized drugs

20.  Bioinformatics is a scientific discipline that
encompasses all aspects of biology,
computer science and mathematical
models.

21. GENOMIC TECHNOLOGIES
PROTEOMICS
 The study of protein expression and function.
 The aim is to profile the proteins from a cellular or
tissue source.
 Comparative studies are done (protein expression in
healthy and diseased states).
 2D polyacrylamide gel electrophoresis and mass
spectroscopy are widely used to study protein
expression.
 Proteomics gained more importance because of …
• the belief that gene-based studies alone are inadequate
for drug discovery;
• the observation that disease processes and treatments
are manifested at the protein level.

22. Applications of proteomics
 Provides a protein profile of a cell or tissue that can be
used comparatively (healthy vs diseased state);
 The protein differences discovered are used for the
development of new drugs or drug targets;
 Identification of diagnostic markers for certain disease
states.
• Eg.: Identification of the biomarker psoriasin from
the urine of patients with squamous cell carcinoma
of the urinary bladder. This protein is normally not
found in the cells of the urinary tract in healthy
individuals.

23. Transcriptomics
 Involves large scale analysis of mRNAs in order to
better understand when, where and under what
conditions genes are expressed.
Structural genomics
 Generating 3D structures of one or more proteins from
each protein family to understand the biological targets
for drug design.
‘Knock out’ studies
 An experimental method to understand the function of
DNA sequences and the proteins they encode.
 Researchers inactivate genes in living organisms and
monitor any changes that could reveal the function of
those genes.

24. Comparative genomics
 Comparative analysis of the DNA sequence patterns of
humans and well-defined model organisms (animals).
 Powerful tool in identifying human genes and
interpreting their function.
Microarray
 Is a ‘multiplex lab on a chip’
 Collection of microscopic DNA spots attached to a solid
surface
 It is a 2D array on a solid substrate (glass slide or
silicon thin-film cell) that assays large amounts of
biological materials.

26. FOR YOUR INFO …

27. • Stereoisomers: Two molecules are described as
stereoisomers of each other if they are made of the same
atoms, connected in the same sequence, but the atoms are
positioned differently in space. The difference between two
stereoisomers can only be seen when the three dimensional
arrangement of the molecules is considered. E.g., ‘Cis’ and
‘trans’ forms.
• Enantiomers: Pair of molecules that are mirror images of each
other. E.g., amphetamine and dextroamphetamine
• Genome: The genetic material of an organism, encoded either
in DNA or, for many types of viruses, in RNA. The genome
includes both the genes and the non-coding sequences of the
DNA/RNA.
• Proteome: The entire protein complement expressed by a
genome or cell or tissue.

28. THANK YOU