Importance of Stereochemistry in Drug Design.pptx

Vision: To Pursue Excellence in Pharmaceutical Education & Research to Develop Competent Professionals 1
Presented by
Yogesh Kailas Chaudhari
M. Pharm (Pharmaceutical Chemistry )
A seminar as a part of curriculum requirement for 1st year M. Pharm 1st semester
Academic Year: 2023-2024
Shri Vile Parle Kelavani Mandal’s Institute of Pharmacy, Dhule
Topic: Importance of Stereochemistry in Drug Design
Year of the Study: First Year M. Pharm (Pharmaceutical Chemistry)

Vision: To Pursue Excellence in Pharmaceutical Education & Research to Develop Competent Professionals
Index
Sr.no. Particulars
1) Introduction
2) Stereochemistry
3) Important definitions
4) Clinical Relevance of Stereoselectivity
5) Importance of the chirality in drugs
6) PK/PD stereoselectivity
7) References
2

Introduction
‘’ Stereochemistry is a branch of chemistry that deals with the
spatial arrangement of atoms and groups in molecules.’’
 Chiral chemistry was introduced by Louis Pasteur when he
separated two isomers of sodium ammonium tartrate in 1848 for the
first time.
 Later it was known that chirality not only plays role in life of
plants and animals but it also shows a profound role in
pharmaceutical, agricultural and other chemical industries.
 Chirality matters very much in pharmaceutical sciences as most of
the pharmaceuticals are chiral where if one mirror form provide
desired therapeutic effect then the second one may be inactive or
may provide lesser or even better therapeutic actions, in certain
cases the second mirror form can show toxicity and adverse effects.
In pharmaceutical science 56% of the drugs used are chiral and
88% of the last ones were marketed as racemic mixture of two
equimolar enantiomers.
3
International Journal of Applied and Basic Medical Research
3(1):p 16-18, Jan–Jun 2013. | DOI: 10.4103/2229-516X.112233

IMPORTANT DEFINITIONS
• CHIRALITY:
A chiral molecule/ion is non-superposable on its mirror
image. The presence of an asymmetric carbon centre is
one of several structural features that induce chirality in
organic and inorganic molecules.
• STEREOISOMERS:
Isomers that have same molecular formula and
connectivity but differ in a way that atoms are oriented in
space - i.e; Difference between isomers lies only in 3D
arrangements of atoms.
4
3(1):p 16-18, Jan–Jun 2013. | DOI: 10.4103/2229-516X.112233

ENANTIOMERS:
Greek word: enantio: opposite
merons: parts
Stereoisomers with non-superimposable
mirror images.
DIASTEREOMERS:
Diastereomers are stereoisomers that are not
mirror images of one another and are non-
superimposable on one another.
Stereoisomers with two or more stereocenters
can be diastereomers.
Types of Stereoisomerism
5

1.Configurational isomers
(a)Geometric isomers:
#Cis & trans system /E & Z system
Cis–trans isomerism, also known as geometric isomerism, describes a certain arrangement of
atoms within molecules. The prefixes "cis" and "trans" are from Latin: "this side of" and "the
other side of", respectively.
6
3(1):p 16-18, Jan–Jun 2013. | DOI: 10.4103/2229-516X.112233

#Relative configuration / Fischer projection (L & D configuration)
(b) Optical Isomers:
7

ABSOLUTE CONFIGURATION
#R & S CONFIGURATION
• Priority of an atom is determined by its
atomic number
• Order of substituents going from highest
to lowest priority.
• Clockwise-R (rectus).
• Anticlockwise - S (sinister).
• Unless established experimentally no idea
whether (+) or (-) rotation is associated
with R or S configuration.
8
3(1):p 16-18, Jan–Jun 2013. | DOI: 10.4103/2229-516X.112233

(b) Conformational Isomers:
Conformations or conformational isomers have different spatial arrangements of atoms of a
molecule but have same bond connectivity and the same configuration, if chiral. These
different arrangements are obtained by rapid rotations around single bonds, resulting in
changes of dihedral angles between the concerned vicinal groups.
9

CHIRALITY OF DRUGS
• Chiral center arises when a carbon atom has four structurally different groups attach to it.
• When a compound contain one or more chiral center it is able to rotate plane polarized light
to the right (+) or the left (-).
• E.g. Adrenaline can exist as two Enantiomers that are mirror images of each others and
thus known as non-superimposable.
ADRENALINE
• Adrenaline Enantiomers have identical physical and chemical properties, the only in their
properties is that the Enantiomers rotate plane polarize light in opposite direction, both
Enantiomers have different biological properties.
• The negative Enantiomers exert a stronger effect i.e. Heart rate increases.
• The device which is used to determine the direction in which a molecule rotate plane polarize
light is polarimeter.
• X-ray crystallography of adrenaline Enantiomers that negative form has R configuration and
positive the form has S configuration.
Singh et al., IJPSR, 2014; Vol. 5(11): 4644-4659.
10

Clinical Relevance of Stereoselectivity
1.Individual Patient Response
The stereoselectivity of a drug can result in different
therapeutic benefits and side effects for different
patients, emphasizing the importance of personalized
medicine in clinical practice.
2.Drug Interactions
Drug-drug interactions can alter the pharmacokinetic
and pharmacodynamic behavior of drugs, leading to
changes in their stereoselective effects. This can lead
to altered therapeutic and toxic effects of drugs that can
be unpredictable.
11

Importance of the chirality in drugs
 This stereoisomerism results in different physical and chemical properties of the compound.
 If this compound happens to be drug then it results in different pharmacokinetic and
pharmacodynamic properties.
 The importance of chiral drugs in the drug development space cannot be understated.
 In pharmaceutical industries, 56% of the drugs currently in use are chiral molecules and 88% of
the last ones are marketed as racemates (or racemic mixtures), consisting of an equimolar mixture
of two enantiomers.
12

Thalidomide-disastrous biological activity of the wrong enantiomer
 In 1960 in Europe, racemic thalidomide was given to pregnant
females to cure morning sickness.
 This led to deformations in babies and neurotoxic effects.
 These were due to S-thalidomide.
 R-thalidomide contained the desired therapeutic activity.
13

 The enantiomers of a chiral drug differ in their interactions with enzymes, proteins,
receptors and other chiral molecules too including chiral catalysts.
 These differences in interactions, in turn, lead to differences in the biological activities of the
two enantiomers, such as their pharmacology, pharmacokinetics, metabolism, toxicity,
immune response etc.
 Surprisingly, biological systems can recognize the two enantiomers as two very different
substances.
14

Importance of Chiral Drugs in Biological System
 Chirality has played a significant role in drug synthesis and production. The majority of the
medicines that have been found are chiral. The association of drugs with biological targets
such as proteins, nucleic acids, and bio membranes determines their pharmacological
function.
 One enantiomer of a chiral drug may be a treatment for a specific condition, whereas the
other enantiomer may not only be ineffective but also poisonous.
 As a result, Chirality is crucial in drug development. In the design and synthesis of drugs,
synthesizing a compound as a single enantiomer is important.
#Both enantiomers act on the same biological target(s), but one isomer has higher binding
affinity than the other
 For example, carvedilol is marketed as a racemate for the treatment of hypertension and
congestive heart failure.
 It is a nonselective ẞ- and a- adrenergic receptor blocking agent.
 Nonselective ẞ blocking activity resides mainly in the (S)-carvedilol, and the α-blocking
effect is shared by both (R)- and (S)-enantiomers.
 Sotalol is a racemic ẞ-adrenergic blocker.
 The (R)-enantiomer possesses the majority of the ẞ-blocking activity, and the (R)- and (S)
enantiomers of Sotalol share an equivalent degree of class III antiarrhythmic potency.
15

Both enantiomers act on the same biological target, but exert opposed
pharmacological activities
For example, (-)-dobutamine demonstrated an agonistic activities against α- Adrenoceptors,
whereas its antipode (+)- dobutamine is an antagonist against the same receptors.
The (+)- dobutamine is also acts as an ẞ1-adrenoceptor agonist with a ten fold higher potency
than the (-) isomer and is used to treat cardiogenic shock.
Chiral Carbon
16

PHARMACOKINETIC & PHARMACODYNAMIC STEREOSELECTIVITY
Many drugs used in clinical practice contain one or more chiral centers. These chiral drugs are often
used therapeutically either as pure stereoisomers or as a racemic mixture. The three dimensional
interaction of two enantiomers with a macromolecule, such as an enzyme or receptor, to form
diastereomeric complexes may result in chiral recognition and significant differences in
pharmacokinetic processes as well as the pharmacodynamics.
PHARMACOKINETICS STEREOSELECTIVITY
1.Absorption
• Passive intestinal absorption
• Carrier transporter stereoselectivity
2.Distribution
• Protein binding
• Tissue distribution
3.Metabolism
• First pass metabolism.
• Phase I and II phase metabolism
4. Elimination
• Renal Excretion
17

ABSORPTION AND STEREOSELECTIVITY
Passive intestinal absorption
The absorption and transport of the majority of drugs across biological membranes occur by passive
diffusion, a process dependent upon physicochemical properties, i.e., lipophilicity, ionization, and
molecular size.
Since enantiomers have identical physicochemical properties, stereoselectivity would not be
expected.
18

Carrier Mediated Transporter
 Stereo selective intestinal transporter is the main
cause for marked differences in the oral absorption
of enantiomers.
 Inside L-Methotrexate have 40 fold higher C-max
and AUC than D-Methotrexate
Methotrexate
 carrier-mediated mechanisms, e.g., facilitated
diffusion or active transport, processes involving
direct interaction between a Substrate and a carrier
macromolecule, stereoselectivity is expected.
Preferential absorption of the L- compared to the D-
enantiomers of dopa and methotrexate have been
reported.
19

DISTRIBUTION
Protein binding
 Stereo selective plasma protein binding could
influence distribution and elimination because the
major determinant of drug distribution and elimination
is protein binding.
 The enantiomers may display different magnitudes of
stereoselectivity between the various proteins found in
plasma.
 Ex. The R- propranolol binding to albumin is greater
than S- propranolol and the opposite is observed for
1-acid glycoprotein.
R- propranolol
S- propranolol
20

METABOLISM
First pass metabolism
Stereo-selective drug metabolism is commonly observed in vitro for racemic drugs and can results in
substantial differences in the vivo plasma concentration- time profiles between enantiomers due to
stereo selective bioavailability or drug disposition.
The magnitude of stereoselectivity depends on the metabolic pathways involved drug metabolism.
Phase I and phase II metabolism
Drugs Metabolism pathway Enzyme stereoselectivity
Warfarin 7-Hydroxylation
6-Hydroxylation
8-Hydroxylation
10-Hydroxylation
CYP2C9 (S>>R)
CYPIA2 (R>>S)
CYPIA2 (R>>S)
CYP3A4 (R>>S)
Felodipine Oxidation CYP2C9 (S>>R)
CYP2C19(R>S)
Omeprazole HydroxylationSulfoxidatio
n5-O-demethylation
CYP2C9 (R>>S)
CYP2C19 (R>>S)
CYP3A4 (S>>R)
CYP2C19 (R>>S)
21

Some time the two isomers compete with each other to bind the enzyme binding site, this
result in inhibition the metabolism of the one enantiomer.
(R)-Propaphenone
(S)-Propaphenon
Hydroxyl Group Below
And Above Plane
22

Stereoselectivity in renal clearance may arise as a result of either selectivity in protein binding,
influencing glomerular filtration and passive reabsorption, or active secretion or reabsorption.
Enantio selectivity in renal clearance has been reported for a number of drugs, and in the majority
of instances the selectivity is relatively modest, with enantiomeric ratios between 1.0 and 3.0.
In the case of the diastereoisomers quinine and quinidine, the difference is about fourfold, with
values of 24.7 and 99 mLmin-1in man, respectively.
ELIMINATION
Renal excretion
23

24
PHARMACODYNAMIC
The active enantiomer has a 3-dimensional structure that allows drug domain A to interact
with binding site domain a, B to interact with b, and C to interact with c. In contract, the
inactive enantiomers cannot be aligned to bind the same 3 sites simultaneously. The
difference in 3-D structure allows the active enantiomers to bind and have a biological effect,
whereas the inactive enantiomer cannot.

25
Easson-Stedman Hypothesis
•The Easson-Stedman Hypothesis states that the more potent
enantiomer must be involved in a minimum of three intermolecular
interactions with the receptor surface.

References
1. Rohan Kumar, Maaz Hassan and Karan Pahuja. Effects of Stereoisomers on
Drug Activity. Am J Biomed Sci & Res. 2021 - 13(3). AJBSR.MS.ID.001861.
DOI: 10.34297/AJBSR.2021.13.001861.
2. Singh et al., IJPSR, 2014; Vol. 5(11): 4644-4659.
3. Stephens TD, Bunde CJ and Fillmore BJ: Mechanism of action in thalidomide
teratogenesis. Biochemical Pharmacology 2000; 59(12): 1489-99.
4. Craig B, Scott AF A Handbook of Organic Chemistry by T.W. Graham
Solomons Snyder
5. Simonyi M (1994) Stereo-chemical Definitions and Nomenclature: Changing
signs? From Therapeutic Innovation and Regulatory Science 28(2): 533-540
26

Vision: To Pursue Excellence in Pharmaceutical Education & Research to Develop Competent Professionals 27

Importance of Stereochemistry in Drug Design.pptx

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Importance of Stereochemistry in Drug Design.pptx

Similar to Importance of Stereochemistry in Drug Design.pptx (20)

Recently uploaded

Recently uploaded (20)

Importance of Stereochemistry in Drug Design.pptx