Pharmaceutical Medicinal Organic Chemistry: International of Asia and The Pacific

International of Asia and the Pacific
Pharmacy Department
PHARMACEUTICAL MEDICINAL ORGANIC CHEMISTRY
Drug Design Strategies
IV. Computer-Aided Drug Design (CADD): Early Methods
Initially, the design of new drugs was based on starting with a prototypical molecule,
usually a natural product and making structural modifications. Examples include steroidal
hormones based on naturally occurring cortisone, testosterone, progesterone, and estrogen;
adrenergic drugs based on epinephrine; local anesthetics based on cocaine; opiate
analgesics based on morphine; antibiotics based on penicillin, cephalosporin, and tetracycline.
Today, it is more common to take a holistic approach that, where possible, involves
understanding the etiology of the disease and the structure of the receptor where the ligand
(drug) will bind.
Statistical Prediction of Pharmacological Activity
Just as mathematical modeling is used to explain and model many chemical processes, it
has been the goal of medicinal chemists to quantify the effect of a structural change on a defined
pharmacological response. This would meet three goals in drug design:
a. To predict biological activity in untested compounds
b. To define the structural requirements required for a good fit between the drug molecules
and the receptor
c. To design a test set of compounds to maximize the amount of information concerning
structural requirements for activity from a minimum number of compounds tested
This aspect of medicinal chemistry is commonly referred to as quantitative structure-

activity relationships (QSAR). The goals of QSAR studies were first proposed about 1865 to 1870
by Crum-Brown and Fraser, who showed that the gradual chemical modification in the molecular
structure of a series of poisons produced some important differences in their action.
ED50 is the amount of the drug needed to obtain the defined pharmacological response in
50% of the test subjects. Let us assume that drug A’s ED50 is 1 mmol and drug B’s ED50 is 2
mmol. Drug A is twice as potent as drug B. in other words, the smaller the ED50, the more potent
is the substance being tested.
Partition Coefficient
The most common physicochemical descriptor is the molecule’s partition coefficient in an

octanol/water system. As emphasized previously, the drug will go through a series of partitioning
steps:
a. Leaving the aqueous extracellular fluids;
b. Passing through lipid membranes; and
c. Entering other aqueous environments before reaching the receptor.
In this case, a drug is undergoing the same partitioning phenomenon that happens to any
chemical in a separatory funnel containing water and a nonpolar solvent such as hexane,
chloroform, or ether.
These membranes are not exclusively anhydrous fatty or oily structures. As a first
approximation, they can be considered bilayers composed of lipids consisting of a polar cap and
large hydrophobic tails.
In addition, the membranes on the surface of nucleated cells have specific antigen
markers, major histocompatibility complex (MHC), by which the immune system monitors the
cell’s status. There are receptors on the cell surface where hormones such as epinephrine and
insulin bind, setting off a series of biochemical events within the cell. Some of these receptors
are used by viruses to gain entrance in to cells, where the virus reproduces.
V. Computer-Aided Drug Design: Newer Methods
Because powerful computing power, high-resolution computer graphics, and applicable

software has reached the desktop, computational drug design methods are widely used in both
industrial and academic environments.
Forces Involved with Drug-Receptor Interactions
Keep in mind that a biological response is produces by the interaction of a drug with a
functional or organized group of molecules. This interaction would be expected to take place by
using the same bonding forces as are involved when simple molecules interact.
Three-Dimensional Quantitative Structure-Activity Relationships
With molecular modeling becoming more common, the QSAR paradigm that traditionally
used physicochemical descriptors on a two-dimensional molecule can be adapted to 3D space.
An example of this approach is the Comparative Molecular Field Analysis (COMFA). It is a

3D QSAR technique based on data from known active molecules. The aim of this is to derive a
correlation between the biological activities of a set of molecules and their 3D shape, electrostatic
and hydrogen bonding characteristics.
The COMFA methodology is used in similarity analyses comparing molecular conformers’

ability to bind to a receptor. This is called Comparative Molecular Similarity Indices analysis or
COMSIA. It is similar to COMFA in that the molecules are aligned in a grid, but differs in the type
of indices or descriptors that describe binding to the receptor being the most useful.
Database Searching and Mining
Chemical databases can contain hundreds of thousands of molecules that could be suitable
ligands for a receptor. But, no matter how good the fit is to the receptor, the candidate molecule
is of no use if the absorption is poor or if the drug is excreted too slowly from the body. An
analysis of 2,245 drugs has led to a set of ‘rules” called the Lipinski Rule of Five. A candidate
is more likely to have poor absorption or permeability if:
1. The molecular weight exceeds 500;
2. The calculated octanol/water partition coefficient exceeds 5;
3. There are more than 5 H-bond donors expressed as the sum of O-H and N-H groups; and
4. There are more than 10 H-bond acceptors expressed as the sum of N and O atoms.
The rapid evaluation of large numbers of molecules is sometimes called high-throughput

screening (HTS). Robotic devices are available for this testing. Based on the results, the search
for viable structures is narrowed, and new compounds are synthesized.
Are there Drugs Developed Using the Newer Computer-Aided Drug Design Methods?
Here, the answer is yes. The example of dorzolamide is one. Others include ACE-inhibitor
captopril and HIV protease inhibitors nelfinavir and amprenavir. In reality, modern CADD is used
in combination with structure-based drug design and QSAR. These methods permit the medicinal
chemists to focus more quickly in the structural components that enhance activity and provide
receptor specificity.
End of Lecture
Prepared by ConRPh2023

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International of Asia and the Pacific

Drug Design Strategies

IV. Computer-Aided Drug Design (CADD): Early Methods

Statistical Prediction of Pharmacological Activity

This aspect of medicinal chemistry is commonly referred to as quantitative structure-

The most common physicochemical descriptor is the molecule’s partition coefficient in an

V. Computer-Aided Drug Design: Newer Methods

Because powerful computing power, high-resolution computer graphics, and applicable

Forces Involved with Drug-Receptor Interactions

An example of this approach is the Comparative Molecular Field Analysis (COMFA). It is a

The COMFA methodology is used in similarity analyses comparing molecular conformers’

Database Searching and Mining

The rapid evaluation of large numbers of molecules is sometimes called high-throughput

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