Protein Target Selection

Selecting Protein Targets and Utilizing the Protein Data Bank for Computer-Aided Drug Design

This tutorial will guide you on how to start computer-aided drug design (CADD) by choosing the right protein targets and using the Protein Data Bank (PDB) to get crucial structural information.  This is an essential step in the drug discovery process that sets the stage for later computer-aided drug design studies. 

The Basics: What is a Protein? 🧬

Let us first learn what proteins are and what they are made up of before we start targeting them in computer-aided drug design and discovery.  Proteins are like tiny machines that keep our bodies running and perform some functions in the body.  They are big; proteins perform many things that are necessary for life.  They give cells structure, move molecules around, send signals, and, most importantly for drug design, proteins also speed up chemical reactions as enzymes.

A long chain of amino acids, which are smaller building blocks, make up proteins; they are the basic building blocks of life.  There are 20 different kinds of amino acids, and the way they are put together in a particular order gives the protein its own structure and function. 

The Four Levels of Protein Structure

The unique three-dimensional (3D) structure of a protein is what makes it work and function in the body. This structure of protein can be broken down into four steps/levels of proteins:

Primary Structure: The primary structure of a protein is just the order of the amino acids in the chain. It's like the order of the letters that make up a word (A, B, C ).

Secondary Structure: The secondary structure of a protein is formed when the chain of amino acids starts to fold into regular patterns that repeat. Alpha-helices, which are coils, and beta-sheets, which are folded sheets, are the most common.

Tertiary Structure: This is the 3D shape of a single protein molecule as a whole. The alpha-helices and beta-sheets, as well as other parts of the chain, fold and fit together to form a specific shape that functions effectively. This three-dimensional shape makes pockets and grooves on the surface of the protein. The tertiary structure is the level of structure that is most important to us when designing drugs, i.e, in computer-aided drug design.

Quaternary Structure: Some proteins have more than one chain of amino acids, which are called subunits. This level tells you how the different subunits fit together to make the final protein complex.

Why Target Proteins in Drug Design? 

Proteins perform a wide range of functions. They can be enzymes that speed up chemical reactions, receptors that detect signals from outside the cell, transporters that move molecules, and structural components. The tertiary structure of a protein, or its 3D shape, makes certain areas on its surface special. The active site, also known as the binding pocket, is one of the most essential parts of a protein. This is a cleft with a precise shape where the protein interacts with other molecules to do its job. Most of the time, their job is to bind to another molecule, known as a ligand. This ligand can be a small molecule, like a sugar or vitamin, another protein, or DNA. 

How Do Proteins Function? The Lock and Key Analogy

The main idea behind CADD is that when a protein interacts with a ligand, it forms a "lock-and-key" relationship.

The "Lock" is the protein. Its binding pocket has a certain shape and chemical properties.

The Drug is the "Key": Our goal is to make a small molecule (a drug) that fits perfectly into this binding pocket.

We can change the protein's activity by making a drug that fits tightly into this pocket. Most of the time, the goal is to prevent (block) the protein from doing something that exacerbates a disease. This is why it's so important to have an accurate 3D model of a protein, which we get from the Protein Data Bank (PDB), when making a drug. 

Most drugs are small molecules that are designed to resemble a key.

Inhibition: A drug can attach to a protein's active site, preventing the natural ligand from binding and blocking the protein from performing its normal, often disease-causing function. This is known as inhibition. An example is a drug that stops an enzyme that a cancer cell needs to grow.

Activation: A drug can also bind to a site and act like the natural ligand, which turns on the protein's function. This is known as activation or agonism. For instance, a drug that activates a receptor in brain cells to ease pain.

The goal of structure-based drug design is to utilize the three-dimensional shape of the protein "lock" to create the most effective drug "key."