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Making Medicine: Surprising Stories from the History of Drug Discovery



Making Medicine: Surprising Stories from the History of Drug Discovery PDF

Author: Keith Veronese

Publisher: Prometheus

Genres:

Publish Date: July 15, 2022

ISBN-10: 1633887537

Pages: 250

File Type: Epub, PDF

Language: English

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Book Preface

HOW DOES MODERN DRUG DISCOVERY WORK?

How do scientists design the pharmaceuticals we use to improve our lives? A handful are happy accidents and overlooked mixtures of carbon and hydrogen that become million- and billion-dollar makers for corporations. They also improve the lives of people the world over in the process. While the unintended discoveries in the chapters that follow may appear miraculous, drug discovery, under normal conditions, is a very laborious and rational undertaking. At the core of modern, rational drug discovery is the leveraging of multiple fields together to make one wondrous event happen—the binding of a molecule in the body to relieve a pain, erase an inconvenience, or cure a disease.

What Is the Target of a Drug?

Potential drug targets play a role in a disease state, but they do not have to cause the disease themselves. The positive modification of a drug target, in theory, should result in a biological change (e.g., the breakdown of a cell signaling pathway) that halts the disease or acute problem at hand. How does this modification occur? It’s all about binding, the act of two structures, the drug (often a small molecule) and the target, coming together in hope that a promising result occurs. What is a small molecule? For the purpose of drug design, it is the product of a reproducible chemical reaction that scientists aim to be 500 daltons or less in size. A dalton is a unit of atomic mass that is one-twelfth the mass of a carbon atom. To give some examples, a molecule of water is a little more than eighteen daltons, sodium chloride (table salt) is fifty-eight and a half daltons, a molecule of the pain reliever ibuprofen is just over 206 daltons, and a molecule of the blood pressure drug losartan is just under 423 daltons. Ibuprofen binds to enormous cyclooxygenase enzymes, stopping the 70,000-dalton enzymes from doing their work and bringing pain relief in a matter of an hour. Not bad for a small molecule of 206 daltons.

Ligand-Based Drug Design versus Structure-Based Drug Design

Drug design often revolves around the testing of molecules in hopes of finding one that binds to and stops or alters the action of an enzyme or other biological target and results in a positive effect on the body. There are multiple approaches to drug design, with ligand-based and structure-based being at the core.

Ligand-based drug design lacks detailed knowledge of the structure of the biological target of a possible drug, relying only on previous known information about what binds the target. A ligand, by definition, is a molecule that binds to a larger molecule. In drug design, our ligand is a small-molecule drug candidate. By making rational modifications to other molecules known to bind the target, it is possible to create a more effective small-molecule drug even without knowing the exact structure of the target. This is difficult, however, as researchers are essentially flying blind as they synthesize a number of small molecules in hopes that one will perform superior to previous results.

Structure-based drug design is possible when highly detailed information about the shape and atomic composition of the drug target is known. This is often possible when high-resolution x-ray crystallography data exist, data showing the three-dimensional structure of the target through a mesh of electron clouds, or with high-quality nuclear magnetic resonance (NMR) spectroscopy. X-ray crystallography is an art to itself, relying on scientists to grow a crystal of the desired target at high concentrations of protein and then subjecting the fragile crystal to a barrage of x-rays, often at extremely low temperatures. It is not at all uncommon for a crystal to become damaged in the process, setting back months of work. This work is performed merely to obtain the raw data, which must then be meticulously processed before a three-dimensional structure of the crystalized target is revealed. Access to a well-resolved three-dimensional structure opens the doors to computer-aided techniques in drug design and also aids in the high-throughput screening techniques we will learn about next.

High-Throughput Screening and Its Role in Drug Design

High-throughput screening involves scanning libraries of thousands to millions of small molecules in an assay against an established target to see if they can alter the target in any way. An assay is just a fancy word for a test of any type that can qualitatively or quantitatively measure the change in activity of the target. Each small molecule in the library that successfully attains a minimum threshold for activity in the assay is called a “hit.” These small molecules are often on the scale of 500 or less daltons. Successful hits are screened against other known targets as well to make sure they do not affect them and cause undesirable effects down the line. Due to the sheer size of the small-molecule libraries used in high-throughput screening, testing of compounds is often a job requiring significant automation, with unattended robotic systems capable of assaying and scanning the results of tens of thousands of compounds in a single day.1 If multiple hits are similar in structure, it is likely that additional small molecules will be synthesized through organic chemistry methods with well-known bioisosteric alterations in hope of further increasing the potency against the target. A bioisostere is a group of atoms that behaves similarly either physically or chemically in biological organisms to another set of atoms. This is part of leveraging the structure–activity relationship between the small molecule and the target to create a better binding event.

High-throughput methods can also take place in silico, where small molecules in a digital library are spun and manipulated to see how well they will “dock” with a computer-generated model of a known target. These computer-generated models take into account the amount of space present for the small molecule to attach using chemistry concepts like electron density and hydrogen bonding. The computer-generated models are often informed by earlier successes in x-ray crystallography and NMR spectroscopy. Such tests are extremely processor intensive and are imperfect, but still yield quality results as to what type of molecules may bind to the drug target before any benchtop chemistry or assays are performed.

Akin to high-throughput screen is fragment-based lead discovery, which relies on smaller libraries of compounds (usually in the thousands) and even smaller molecules than used in a high-throughput screen (often less than 300 daltons). These smaller molecule fragments are often successful in binding hard to reach “hot spots” on the target that are impossible for the larger (but still small) molecules used in high-throughput screening to target.2 Once a substantial number of binding fragments are discovered through a series of assays, the fragment can be “grown” to the size of a typical small-molecule drug through rational organic synthesis and the addition of atoms (or functional groups if you have sat through any organic chemistry lectures) that will further aid in the reception of the drug candidate. Also available is the possibility of combining well-performing fragments, especially if their binding to the target overlapped in multiple spaces, in a process scientists versed in fragment-based lead discovery call “merging.” This is one key advantage of fragment-based lead discovery over high-throughput screening, as the two “merged” fragments will still be on the order of less than 500 daltons, approximately the size of a small-molecule drug candidate. There could also be multiple ways to merge two fragments, allowing for multiple small molecules to come out of such a fragment-based study.3

One may start with a library of a million small molecules to arrive at a single lead compound that will be rigorously tested through additional in vitro studies and, as the goal, animal and human clinical trials in the process of drug development. The enormity of this task makes the unintended discovery of the drugs to be discussed later in the book all the more fascinating and serendipitous.

The Role of Natural Sources in Drug Design

Nature is a bountiful source of possible pharmaceuticals due to its diverse environments and the sheer number of defense mechanisms organisms develop to survive. Medicinal chemists, armed with knowledge of the role that specific molecules play in a plant or microbe or even a rare invertebrate that inhabits the bottom of the ocean, often use these identified molecules as starting points for solving similar problems in the human body. For example, a crude extract of willow tree bark has been used for thousands of years to alleviate pain and fever. Throughout time, scientists discovered that the active ingredient in the willow bark extract was a small molecule now known as salicylic acid, which played a role in the immune response mechanisms of the tree. By slightly altering salicylic acid, scientists created acetylsalicylic acid, better known to us as aspirin. Thankfully, we have aspirin to take when a headache or fever arrives and are not left to scour the woods for a willow tree and subsequently concoct a no doubt bitter elixir.

A more recent (and exotic) example is the drug ziconotide (brand name Prialt), which is derived from a toxin present in Conus magus, the cone snail, a venomous sea-dwelling creature that can kill with a sting. The result is a pain reliever quite strong—1,000 times stronger than morphine—yet so delicate that it must be delivered directly into the spinal fluid so as to not be blocked by the blood–brain barrier.4

What Is Bioavailability?

Bioavailability is key to drug design. It is the measure of the amount of drug actually in the bloodstream and open to use by the body compared to the total dose taken. Why would these two be different? Most drugs are taken orally and thus subject to the gastrointestinal tract. This is not all bad, as the pills do need to be dissolved before active ingredients within are released. But within the gastrointestinal tract, there are a number of options for the drug to be metabolized or modified before it reaches the bloodstream and the drug’s desired place of action. Also, if the drug passes through the liver, there is a significant chance for the available, bioactive fraction of the drug to be reduced prior to it reaching systemic circulation. This happens as the liver further metabolizes the drug or excretes it through bile in what is known as the first pass effect.5

One way to get around a significant decrease in bioavailability is to introduce the drug intravenously, but this isn’t exactly an option when you go to pick up your prescriptions at your local pharmacy. Ensuring the ability of a drug to be taken orally is a key thought in the back of the minds of chemists and pharmacologists throughout the design phase, as it increases the ease of taking the medication and does not introduce need for administration by injection, which may limit the market for the drug.


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