Hello everybody and welcome to the course on Drug Target Identification by Insilico

Medicine. We will take you on a journey into the exciting world of pharmaceutical science and
the discovery of new drugs. In this course, we will cover the various methods and techniques
used for drug target identification, starting from traditional approaches to the latest
advancements in computational methods, especially machine learning and artificial intelligence.
Drug target identification is a complex and multidisciplinary field that involves a wide
range of biological and chemical concepts. We will delve into the molecular and cellular
mechanisms of various diseases, get to know several tools for drug target discovery and see
some case studies and finally we will look at the current and future trends in the field. By the
end of this course, you will have a comprehensive understanding of the drug target identification
process and be equipped with the skills needed to tackle real-world problems. Also you will be
provided with an access to PandaOmics, a data-driven, artificial intelligence platform developed
by Insilico Medicine and designed for drug discovery and target identification. The AI-driven
approach of PandaOmics allows researchers to increase the efficiency and accuracy of target
identification, ultimately accelerating the pace of drug discovery and development.

Drug targets
Now let’s start our course with discussing what is a target in the context of drug
discovery. Wikipedia defines a biological target as anything within a living organism to which
some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a
change in its behavior or function. In pharmaceutical research the term "biological target" is
often referred to as a “drug target” to describe those proteins or other biomolecules (such as
DNA for example) to which the drug directly binds modifying their activity and ultimately leading
to a desirable therapeutic effect. Biomolecules that the drug may also bind to, or be metabolized
by, but which are not responsible for its therapeutic effects are not defined as targets.
There are several common classes of drug targets, each with its own distinct properties
and modes of action, which we will cover in detail in the following sections. The largest
biochemical class as drug targets are enzymes. Nearly half of oral drugs on the market have
enzymes as their targets. The most fruitful enzymes for drug discovery today are kinases, a
class of enzymes that catalyze the transfer of a phosphate group from adenosine triphosphate
to other molecules. The second largest class of drug targets are receptors on the surface of the
cell membranes. Approximately one-third of available drugs modulate receptors, including G-
protein-coupled receptors (GPCRs) which have been especially successful for drug discovery.
The third class of drug targets are ion channels, including sodium, potassium, calcium ion
channels. The other classes of drug targets are transporters and nuclear hormone receptors.
The non-protein class of drug targets is represented with nucleic acids.

Drug discovery and Development pipeline

Drug discovery is one of the most complex, risky, and lengthy areas of human
development. This process takes decades, billions of dollars, and fails over 90% of the time.
There are very few truly novel drugs on the market. In 2020, the FDA approved 53 novel drugs,
and that was the record year. Many of these drugs were small molecules that modulated the
function of well-known molecular targets. Discovering a novel molecule for a novel target for a
broad disease indication is extremely rare.
 Target discovery is considered to be the first and most crucial step in the long and
expensive drug development process. The success of the entire process depends on the
identification of an accurate and viable target for drug development. If the wrong target is
selected, it can result in ineffective treatments, adverse side effects, and a significant setback in
the overall drug development process. The identification of a target involves a comprehensive
analysis of the underlying causes of a particular disease and the identification of a specific
molecule or pathway in the human body that can be targeted with a drug. This requires a deep
understanding of the disease process and the latest developments in the field of molecular
biology and pharmacology. It also involves collaboration between scientists from multiple
disciplines, such as biology, chemistry, bioinformatics and machine learning.
Once the target is identified, intensive follow-on research must be conducted to prove
that the choice was correct — a process called "target validation". This includes various studies,
ranging from solving the crystal structure of the target protein to confirming its association with
the disease in question. The association between a target and a disease is a crucial step in drug
discovery that could lead to either the success or failure of the entire program. While every effort
is made to understand the target's role in a disease, the correctness of choice becomes fully
obvious only years later — during clinical trials in humans.
Target identification and validation are followed by discovering ways to influence the
malfunctioning protein — typically by switching it off or changing its activity. This stage involves
large-scale screening programs where thousands or millions of chemical compounds are tested
to see if they can influence the target in a beneficial way. The molecules with acceptable activity
are called "hits." Of these "hits" many turn out to be false positives, and only a small number are
eventually confirmed and selected to become "leads." While lead compounds show significant
activity towards the target of interest, they still need to be optimized for other crucial parameters
— metabolic stability, safety, bioavailability and other properties. The culmination of the lead
optimization process is a molecule or a set of molecules ready for preclinical studies. If the lead
activity and safety are confirmed in animal tests, the molecule is finally nominated as a drug
candidate.
The clinical stage is a new level of commitment that involves high costs, risks, and strict
compliance requirements. Even though drug developers make a huge effort to ensure the
quality of drug candidates, unpredictable side effects сan emerge. This stage is very time-
consuming and expensive, as it requires the enrollment of large numbers of patients in multiple
trials to obtain statistically significant results.
In conclusion, target discovery indeed is a crucial step in the drug development process.