The theory of quantum mechanics developed when the classical theories of mechanics

and electromagnetism were unable to provide explanation to the characteristics of

atomic structure and electromagnetic radiation (Rae, 2008). The appearance of quantum
mechanics resulted in the emergence of a principle that has the ability to describe the
nuclei, proton and neutron (Rae, 2008).

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Quantum theory has two sides, the first is the mathematical side and the second is the
conceptual side. The mathematical side has been successful in estimating the atomic
and subatomic phenomena, while the conceptual side “has been a subject of endless
discussions without agreed conclusions” (Thankappan, 1993).

1.0 Double Slit Experiment

It is known that when particles are emitted through two slits two bands are formed,
while when waves are passed through two slits interference pattern is formed on the
back wall. When the crest of the first wave meets the trough of the second wave, the
two waves cancel each other and destructive interference occurs which result in
appearance of dark lines. On the other hand, when two crests or two troughs of the
wave meet each other construction interference occurs and bright lines are formed.

The elegant difference is blurred by quantum mechanics. When a stream of electrons

passed through one slit, a single band is formed, but when electrons emitted through
two slits an interference pattern is formed, but how could a piece of matters create an
interference pattern like waves? Physicists thought that particles bounced each other
and created the interference pattern. This time they decided to shoot the electrons one
at a time, by this method it is impossible for electrons to interfere with each other. After
a time the same interference pattern is formed. The conclusion was that the single
electron leaves as a particle and becomes a wave of potential then it goes through both
slits and interferes with itself to hit the wall like a particle (The particle is in two places at
once), but mathematically it is even stranger that the electron goes through both slits, it
goes through neither, it goes through just one slit or it goes through just the other. All
of these possibilities are in superposition with each other (Khutoryansky, 2013).
  (Perimeter
Institute, 2012)

Figure 1.0 Double-slit apparatus showing the pattern of electron hits on the observing
screen building up over time.

This made the physicist completely puzzled and they decided to install a measuring
device by one slit to see which slit the electrons actually pass through, but the quantum
world is far more mysterious than they could have imagined. The electron decided to act
differently because it felt that the observer watched it. When they observed the electron,
the electron went back to behave like a little marble, it produced a pattern of two bands
and not many interference pattern as it was expected. Physicists were Perplexed, they
asked what is the matter? Is it Particles or waves? (Khutoryansky, 2013)

After a while they have discovered that, when the electron was observed the wave
function was collapsed.

1.1 The Explanation of double slit experiment

A Physicist called Max Born, one of the founders of quantum mechanics came up with a
new idea for what the wave equation described. Born said that the wave is not a
smeared out of electron or anything else previously encountered in science. Instead, he
declared that electrons are something about a probability wave (Probability
distribution), that is Born argued that the size of the wave that any location predicts the
likelihood of the electron being found there. Where the wave is big that is not where
most of the electrons are, that is where the electrons are most likely to be, and that is
very strange, so the electron on its own sees a jumble of possibilities (Khutoryansky,
2013). “You are not allowed to ask where is the electron right now, but you are allowed
to ask if I look for the electron in this little particular of space, what is the likelihood I will
find it there, and that bugs anyone!”(Peter Fisher, 2012).
Finally, it is shown that the implication of this experiment is that matter can have both
wave and particles properties. This is known as “Wave-Particle Duality” or “Dual Nature
of Particles” This is proposed by Louis de Broglie in 1923 leading to the birth of modern
day quantum mechanics. Exhibiting particles or waves characteristics depends if a
detector is observing the matter or not. The second implication of the double slit
experiment is that the outcomes of macroscopic events can be affected by observation.
This is because macroscopic objects are composed of microscopic particles acting as
either waves or particles (Lejuwaan, 2010).

These facts lead to the emergence of De Broglie equation as shown in (1.1) and (1.2)

 (1.1)

 (1.2)

Where  is the wavelength,   is Planck’s constant,   is the frequency, and E is the total
energy of the particle (Phillips, 2003).

The equations (1.1) and (1.2) are equivalently equal to

 (1.3)

 (1.4)

Where   is the modified Planck’s constant ( ), k is the angular wave number (
and   is the angular frequency (  (Phillips, 2003).

The comparison between planets in a solar system and electrons in an atom was no
longer reasonable. De Broglie’s hypothesis led to the development of quantum
mechanics and subsequently the Schrödinger equation.

It is important to know the equations (1.1) and (1.2) to understand the concept of the
Schrödinger equation that will be discussed in the next section.

2. The Schrödinger wave equation

Quantum mechanics is all about solving the Schrödinger equation. There are many
Schrödinger equations, each physical scenario for which you want to apply. Quantum
mechanics has its own Schrödinger equation, they are all slightly different and all
require slightly different solution techniques. The reason why there are many different
Schrödinger equations is that the situation over under which you want to solve the
Schrödinger equation enters the Schrödinger equation as a potential function and we
know that potential function influence the physics of quantum mechanics.

The Schrödinger equation is a wave equation that describes the behavior of particles by
taking account the fact that matter also has these wave-like properties. “The role of the
Schrödinger equation in quantum mechanics is analogous to that of Newton’s Laws in
classical mechanics. Both describe motion. Newton’s Second Law is a differential
equation which describes how a classical particle moves, whereas the Schrödinger
equation is a partial differential equation which describes how the wave function
representing a quantum particle ebbs and flows. In addition, both were postulated and
then tested by experiment” (Phillips, 2003). The Schrödinger wave equation helped in
the emergence of quantum mechanics and Erwin Schrödinger was the reason of
establishing an equation that considered as one of the fundamentals of quantum
mechanics (Freiberger, 2012).

There are two forms of the Schrodinger equation, the first form is time dependent
Schrödinger equation and the second form is time independent Schrödinger equation
(The Schrodinger Wave Equation, n.d.).

2.1 Time dependent Schrödinger wave equation:

 (1.5)

Where   is the imaginary unit,   is the modified Planck’s constant ( ),   indicates
a partial derivative with respect to time t,   is the wave function of the quantum system,
and   is the Hamiltonian operator (Wikipedia, 2014).

 (1.6)

Where m is the mass of particle, V is the potential energy and   is the Laplacian.

The equation (1.5) is the general equation, while the equation (1.6) is the “single non-
relativistic particle” of the time dependent Schrödinger equation. By solving time
dependent Schrödinger equation, we can determine the probability of detection of
particle in some region as a function of time (Phillips, 2003).

2.2 Time independent Schrödinger wave equation:

Time independent Schrodinger equation is used more than time dependent Schrodinger
equation, because the time is measured on a small scale. “The time-independent
Schrödinger equation predicts that wave functions can form standing waves,
called stationary states” (Wikipedia, 2014). The time independent Schrödinger equation
has another important use that is making the time dependent Schrödinger equation to
be solved easily once the stationary states are predicated by the time independent
Schrödinger equation (Phillips, 2003).

Eψ  (1.7)

 (1.8)

The equation (1.7) is the general equation, while the equation (1.8) is the “single non-
relativistic particle” of time independent Schrödinger equation.

3. The Role of Quantum Mechanics in Structure-Based Drug Design

Most drugs are very small molecules compered to their targets that are enzymes. In
order for drugs to take its effect it has to bind to the active site of the enzyme. We can
think about this as an engine that has moving parts that moving, and a little drug get
stuck in the gears of the engine and hence the entire engine stopped working. This is
how drugs are working. In order to design drug pharmaceuticals must know much
information about the active site of the enzyme; it will help them a lot if they have a very
high-resolution structure so they can know the active site of the enzyme. There are
important enzymes whose structure is strange such as catalase which shown in figure
(1.9) and it will be easier to design drugs if the structure of the active site is known
(Kalyaanamoorthy and Chen, 2011).

Over many decades, specialists used the high technological abilities to displace the hard
obstructions that they faced along the path of drug discovery.

This allowed them to improve the methods of drug design (Kalyaanamoorthy and Chen,
2011). There were many computational approaches that used at different stages of drug
design process. These computational approaches were successful in decreasing the
number of ligands (“a molecule such as drug that binds to receptor” (Dictionary.com,
2014).) In addition, in form the computational approaches helped in reducing the period
and costs of drug discovery.

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The computational approach that we will discuss about is the structure-based drug
design (SBDD). It is a method that depends on 3-D structures of biological targets.
SBDD has two phases; hit identification and lead identification. The first phase is about
exhibiting powerfulness against the target by the recognition of chemical compounds
called “hits”. “Whereas, the latter engages evaluation of the screened hits to identify the
promising lead molecules before proceeding toward a large-scale lead
optimization”(Kalyaanamoorthy and Chen, 2011). On of the most successful examples of
the history of SBDD is the development of human immunodeficiency virus (HIV)
proteinase inhibitor (Meyer and Swanson et al., n.p.).

3.1 Target Identification

Identifying the right target is only the first stage of a long process. Scientists need to
find a protein or gene that is associated with the disease (Kalyaanamoorthy and Chen,
2011). Proteins come from genes, and it is easier to study genes than to study proteins.
One approach to find a new drug target, involves comparing the genes of healthy
individuals with those of people with the disease. The differences between two genetics
maps can help to generate hypotheses in which proteins or lack of thereof cause the
disease. It is also possible to do the opposite, by changing one gene at a time in cells or
simple organisms, and then observing the resulting effects that will happen, so it called
the phenotype of the mutation. If the phenotype has some similarity with the disease’s
states, it can give ideas about the possible relation between the mutated gene and the
disease. The third approach of target identification is to start already with a bioactive
substance such as a natural medicine used in traditional medicine, a compound from
basic research or known drugs with unexpected effects (Kalyaanamoorthy and Chen,
2011).

When targets are identified they, another process occurs which called drug validation.
Drug validation is on of the most important steps in SBDD; many drugs that failed were
because it was not checked by “drug validation process” (Hughes and Rees et al., 2011).
When the target and the active site have been identified then the hit discovery process
starts. One of the successful validation tools is the transgenic animal (animals that carry
foreign genes) as they allow observing the phenotypic endpoints (Hughes and Rees et
al., 2011).

3.2 Hit Identification

When the targets are discovered and being checked for target validation, the next step
is hit identification. Hit identification is about getting a small molecule that has some of
the initial properties that pharmaceuticals want in their final drugs. It is very early in the
process of a drug discovery. The “hit” is defined as a molecule that binds to the target.
There are some ways that used to determine identify the hit. One way is to start with a
natural substrate and to make it drug-like. The second way is to design a De novo hit by
SBDD. This way works if pharmaceuticals are familiar with the binding site as well as the
protein structure. High throughput screening (HTS) is a process that aims to find
inhibitors for the targets by using rapid assays. With HTS there is no need to be familiar
with the nature of chemotype likely to have activity at the target protein (Hughes and
Rees et al., 2011). HTS is considered as one of the main processes for hit identification
(Hughes and Rees et al., 2011). The disadvantage of HTS is that it requires a lot of
materials and time to do a huge combinatorial space (high cost) (Hughes and Rees et
al., 2011). When starting with HTS pharmaceuticals need to screen a lot of molecules to
find a drug. HTS screens more than hundred thousand to million compounds or even
more than a million compounds (Hughes and Rees et al., 2011). Most of the molecules
will not be active against the “biology”, while a large number of molecules will be active
against the “biology” and the process keeps going until there is only one molecule that
is active against the “biology”

3.3 Hit to Lead Phase

“Hit to lead” phase is an elevated level of SBDD phases. It helps pharmaceuticals to get
closer to a drug that is safe and efficacious in people because it helps to identify
compounds with improved potency (Hughes and Rees et al., 2011).

“A lead compound is a compound that demonstrate a desired a biological activity on a

validated molecular target” (Pharmacelsus GmbH, 2013). The key thing about the hit to
lead phase is to identify compounds that is not only binds to the protein, but they in
fact work inside a cell, and they show the selectivity in a cell (Hughes and Rees et al.,
2011). The key aspect of hit to lead stage is a repeated process in which it not only
shows that the compound works in a biochemical assay, but it also demonstrate that it
works effectively and selectively in a cell-based assay (Hughes and Rees et al., 2011).
Therefore, it can go through the cell membrane, reach the target inside the cell, and
engage that protein in a cell-based assay. In starting the hit to lead phase, the
compounds start off with potencies that are weaker than pharmaceuticals would like.
What pharmaceuticals looking for is compounds that will make the medicinal chemistry
that will improve the potency of the hit compound at least a factor of ten, and ideally a
factor of twenty in the biochemical assay (Kalyaanamoorthy and Chen, 2011). Also,
pharmaceuticals look for things to start off with from the hit stage that have weak
cellular potency, but with medicinal chemistry that correlates with the biochemical
potency mentioned above (Kalyaanamoorthy and Chen, 2011). Furthermore, it drives the
cellular potency to be more potent in the cell. This is all toward the goal that
pharmaceuticals want to get potent compounds that are cell active.

Also, there are several other important properties such that, if Pharmaceuticals do not
want the compound to bond to other off-target that may cause toxicity then they prefer
compound to have potency that at least ten-fold weaker to the closest related target.
We will not discuss in detail.

Knowing the active site is a very important thing in drug designing, there are several
ways that used to determine the active site for unknown drugs active sites.

4. Quantitative Structure-Activity Relationship (QSAR)

The quantitative structure-activity relationship (QSAR) is considered as one of the

earliest approaches to drug design. This approach is all about finding a relationship
between how active the compound is as a drug and the physical activities of the
compound. The fundamental principle of QSAR is that the change in structural
properties of the compound can lead to a change in the biological activities of the
compound. QSAR allowed us to determine where approximately the drug settles in the
human body. This is determined by a physical property that used which called the
distribution coefficients between octanol and water (is the ratio between the
concentration of a compound in the mixture). “QSAR depends on bulk properties of the
potential drug molecules” (Moore, 2002). A new method is emerged, it is called 3D-
QSAR, 3D-QSAR is considered to be an effective tool in the design of pharmaceuticals
drugs that helps to connect the activity of a molecule with the properties that depends
on a special part of the molecular structure. We superimpose by a computer a set of
molecules that we know their activities. By this method, the set of molecules with similar
groups will be in the same place. Furthermore, a small box is drowned that divided into
lattice of n points along each side and 200pm apart from each other (Moore, 2002). The
box contains all the molecules. A box containing one molecule is shown in figure 2.0

5.1 QM/MM studies of pharmaceutically relevant targets

In this section we will discuss about an experiment that Alessio and Marco (2012) did to
show that QM/MM could predict the binding orientation of a reference inhibitor. The
experiment is all about the interaction of fatty acid amide hydrolase (FAAH) and
carbamic acid aryl ester inhibitors (URB524) (Lodola and De Vivo, 2012, pp. 337-362). “In
general, SBDD depends on the accuracy of ligand docking, and the ability to identify
binding modes” (Lodola and De Vivo, 2012, pp. 337-362). When FAHH is docked with
URB524 inhibitors, there are two possible of this docking. Tools that applied in drug
discovery were not able to distinguish between the two binding orientations. On the
other hand, when QM/MM was used to model the inhibitor binding process, it made
such a good success in revealing that (Lodola and De Vivo, 2012, pp. 337-362).

QM/MM calculations showed that, the second orientation was energetically preferred.
This QM/MM calculation’s suggested that the notably higher barrier in the first
orientation led to an unstable product. (Lodola and De Vivo, 2012, pp. 337-362). By
QM/MM we can gain a detailed understanding of the binding site interactions, and
hence QM/MM can contribute practically to drugs design.

On the other hand, although QM/MM gives a detailed understanding of the binding site
interactions, QM/MM has not yet played an important role in drug designing. Due to
the high computational abilities that QM/MM has, it looks like that QM/MM will be a
main and an indispensable tool in drug design in the recent years.