Importance of molecular modeling in drug design
and discovery
Introduction
Essential tool to the medical chemist in the drug design.
It is a scientific application for drug design that describes
the generation and representation of 3D structure of
molecules with associated physic-chemical properties.
Mol. Mod. Can combine computational chemistry and
computer graphics.
Mol. Mod. Techniques are derived from the concepts of
molecular orbitals of Huckel, Mullikan and classical
mechanical programs of Westtheimer, Wihery and
Boyd.
Mol. Mod in Drug design plays an IMP role in Drug
Discovery process
Molecular models allow us to "think like a molecule". See
& feel what a molecule feels. And these models provide a
window on the molecular world.
Drug discovery :
The time from conception to approval of a new drug is
typically 12-15 years with estimated cost of $1.2 B !!.
Discovery stages and strategies :
1- define target
2- define lead (is the one that has basic structural
requirements for exhibiting the desired action)(prototype
with observed pharmacological activity)
3- optimize lead
4- refine and formulate lead
5- prove safety and efficacy
Molecular modeling :
I) physical models:
Physical models such as three commercial kits can be very
useful three-dimensional aspects of molecular structure.
But these physical
limitations, being :
models
also
have
significant
Bulky
Can be delicate
Difficult to manipulate
Difficult to fine tune
Static
II) computer graphics :
-High speed computers even on a laptop allow
sophisticated graphics that were unheard of ten years ago.
Products such as Discovery Studio Viewer Pro allow
integration of molecular graphics into documents,
presentations, and World Wide Web pages.
-Computer graphics offer an opportunity to represent
molecular structure in a variety of views for : internal
discussions, presentations, and publication.
"Graphics provided the link between computer
professionals and traditional laboratory chemists"
Drug Development By Molecular Manipulation:
Modification of lead compound (prototype) to more
active, less toxic & more bioavailable analogues by
general process, special process, or prodrug.
1- drug dissection or drug simplification (general)
To provide:
a) Less bulky molecules
b) Less expensive
c) More potent
d) Simple for synthesis
Ex. Morphine (lead compound of plant origin)
simplification pethidine (less addictive on CNS)
2- molecular association = molecular conjunction:
(general)
To
enhance
properties.
pharmacokinetic
&
pharmacodynamic
Small active moieties association through covalent bond
complex or large molecule.
3- Alternation of flexibility & Dimension of lead:
(special)
I) ring opening
Ex. Estradiol (estrogen hormone & contraceptive, inj.)
Diethylstilbesterol (oral contraceptive & in prostatic
cancer- less expensive)
II) ring contraction
Ex. Barbiturate (nonselective sedative, hypnotic
anticonvulsant) phenytoin (selective antiepileptic)
4- molecular addition: (special)
Association through electrostatic attraction or H- bonding
Ex. Amoxycillin-Clavulinate K (Augmentin)
*Amox. ( lactamase unstable)
&
5- introduction
shielding
of
obstructive
group
&
steric
Objectives for:
a) Duration of action
b) Metabolic stability
Prodrugs
Inactive drug, activated in vivo by metabolic hydrolysis.
Objectives of prodrug design:
1- to absorption (bioavailability)
Ex. Dipivaloyl ester of epinephrine to corneal abs.
2- to patient acceptability
Ex. Chloramphenicol (bitter taste) chloramphenicol
palmitate (without bitter taste)
3- to toxicity (side effects)
4- to prolong duration of drug action
5- to avoid drug instability : to avoid 1st pass metabolism.
6- for site specific distribution (drug targeting)
Molecular Modeling & Drug Discovery
The average cost of developing new drug molecules and
the time taken to market them is pretty high. Although the
time factor is getting reduced but the cost factor is
increasing further. Reasons for the growing expenses of
pharmaceutical companies include the investments
needed for the new high throughput research
technologies [1] and for increase in the number of
studies required for new drug molecules [2].
However, even with the growing cost, the number of new
drugs coming to market has shown only a marginal
increase. One of the reasons for this trend could be lack of
structural information about the target molecules. In the
drug design process enzymes are frequently the target of
choice because of their involvement in various biochemical
pathways in human physiology. Even with enzymes, there
can be problems in obtaining their structural information.
Sometimes it is difficult to isolate or produce sufficient
quantities of the target enzyme to study it directly. These
obstacles hinder the successful entry of drug candidates
into market.
Therefore, there is an imperative demand for efficient
methods that could enhance the drug discovery process.
Computational methods for molecular modeling techniques
can be utilized to accelerate drug discovery process for
obtaining new drug molecules. Today, almost every multi-
national
drug
company
and
Contract
Research
Organization (CRO) involved in drug discovery has adopted
computational methodology in different stages of the
design process. Many computational methods complement
one another and may be combined to help rationalize the
drug discovery process. The ultimate challenge in drug
design is to predict and explain activities of new drug
molecules [3]. Modern drug discovery is multidisciplinary
project, where the role of various computational methods
is to utilize experimental and predicted information in
designing new active compounds thereby facilitating and
enhancing the rate of discovery of appropriate chemical
entities for lead optimization. As for as success stories of
drug molecules generated through molecular modeling is
concerned, it has been claimed that structure-based drug
design methods have already contributed to the
introduction of some drug compounds into clinical
trials and for drug approval [4,5].
Currently two major molecular modeling strategies are
employed in drug design process, ligand-based drug
design and structure-based drug design.
Ligand-based drug design (LBDD) :
if structure of targets is not known, but structure of
inhibitor is known.
Structure-based drug design (SBDD) :
If structure of the target (enzyme or protein) is known.
