A Pharmacology Primer

1. Dr. Kenakin, your extensive background in both academic and industrial pharmacology research uniquely positions you to write a book like "A Pharmacology Primer." Can you share what inspired you to write this book and how your experiences influenced its content?

Actually, the beginnings of this book were instigated by a need to educate newly hired biology and chemistry staff who had no background in pharmacology when they joined the company where I worked, GlaxoSmithKline. We realized there was no source of information and I wrote the course which then became a book.

Other books simply discussed the use of drugs for treatment of various ailments but not how to make and improve them.

2. In your book, you emphasize the application of pharmacology in drug discovery. What are some of the most significant changes you’ve observed in this field over the years, and how does the 6th edition address these changes?

Pharmacologists are almost always working in systems they do not fully understand… physiology and Nature still hold many mysteries. This being the case, pharmacology is uniquely based on new technologies to unveil these new secrets of physiological system and thus, it is a fast paced field of endeavor requiring regularly updated information.

Genomics, bio and chemoinformatics, structural biology, highthroughput technologies, and virtual screening have transformed pharmacology in the past few years and technologies such as AI promise to do more of this.

3. One of the key themes in your book is the breakdown of complex discovery techniques. Could you elaborate on how binding, functional, orthosteric, and allosteric assays contribute to quantifying drug effects and their therapeutic applications?

These are the building blocks of Pharmacologic research that form the framework of discovery. Two fundamentally different approaches to the study of drug-target interaction are through binding (physical measurement of molecules binding to protein) and function (measuring the cellular consequences of drugs binding to targets). Each of these have their strengths and limitations and yield complimentary information.

Two other fundamentally different approaches measure the actual interactions of molecules and targets: orthosteric and allosteric. Orthosteric basically measures the ‘steric hindrance’ of bodies interfering with each other as they compete for a common binding site. Allosteric is where drugs bind to a separate site on the target to modify physiology through changing the shape of the protein.

4. The book discusses the use of new technologies for screening, such as virtual, DNA-encoded libraries, and fragment-based approaches. How have these technologies revolutionized the process of drug discovery, and what future advancements do you foresee in this area?

Basically all of these technologies have drastically increased the scope and capacity to test vast numbers of chemical structures. Before the advent of these technologies, libraries of thousands of compounds could be tested with robotic screening; with these new approaches, millions to billions of new structures can now be tested and this radically enhances the chances of finding fruitful binding ‘hits’.

It is defensible to say that probably now any target in physiology can be ‘drugged’ (i.e. a molecule found that binds to it).

5. You’ve highlighted phenotypic (target agnostic) screening for new leads and the determination of drug targets in this edition. Can you explain the importance of this approach in modern drug discovery and its potential impact on the industry?

Two basic approaches to screening are ‘target-based’ (where a biological target is identified and then molecules tested for binding) and ‘systems-based’ where a complex system is subjected to a myriad of molecules to explore the impact on the system.

The aims of these approaches are different; target-based approaches are designed to yield new drug molecules while systems-based approaches may do this but really are primarily designed to explore new mechanisms in physiology that can be manipulated chemically with molecules. Thus, systems screening can yield new approaches to therapy that would not be evident with target-based approaches.

6. Pharmacokinetics and early safety are crucial aspects of drug development. How does your book address these topics, and what are some key considerations for researchers in ensuring new drugs cause no harm while being effective?

If a biologically active molecule cannot access the tissue in the body where the therapeutic need resides or if, when it does, it causes more harm than good, then it is useless as a therapeutic drug. Thus, pharmacokinetics (the study of drug absorption, distribution, metabolism and excretion) are critical to the discovery process.

Similarly, although drug safety takes the fore in late stage drug candidate development, it also plays a pivotal role in early development.

For example, in a recent program for HIV-1 treatment for AIDs, the candidate chemical scaffold was tested in the hERG assay and found to have fatal cardiac activity. There would be no sense in further developing this scaffold until this harmful property was eliminated through medicinal chemistry to the program did this before continuing to optimize the primary effects on HIV-1.

7. The concept of receptor theory and allosteric protein function is central to your research interests. How do these concepts play a role in the strategic drug discovery techniques presented in your book?

Drug mode of action is determined mainly by comparing drug effect to mathematical models. These explicitly define how the drug works and also provide theoretical predictions that can be tested with further experimentation.

This is especially important in pharmacology since drugs are discovered and studied in test systems (not the therapeutic ones) and predictions of activities in other systems (including the therapeutic one) must be inferred until testing in humans is done.

An especially fruitful area of such modeling is in the allosteric nature of proteins since these complex effects have to potential to provide molecules with a wide range of effects not possible through simple steric hindrances systems.

8. Your book includes new material on target engagement and demonstrating the physical interaction of molecules with drug targets. Could you provide an example of how this process works and its significance in the context of drug discovery?

In the beginnings of Pharmacology, much was inferred from the exposure of drugs to tissues, observing a response and then having to assume that a specific interaction took place to cause that response.

With modern techniques to actually prove a physical interaction, a greater detailed knowledge can be gained which can be used to optimize such interactions and make better drugs. Often, the target for a molecule may not be known and thus isolated testing of the interaction of a molecule with the isolated target could be useful.

Thus, techniques such as CETSA (Cellular Thermal Shift Assay) or Isothermal Titration Calorimetry can identify specific interactions and allow more detailed analyses of drug binding.

9. With advancements in genomics, CRISPR, and mRNA therapies, how has the landscape of drug discovery evolved, and what role do these technologies play in the strategies outlined in your book?

As stated previously, pharmacologists are often working in uncharted physiological territory and specific modification of that territory through techniques such as PROTAC or CRISPR to remove components of systems or mRNA to add components can be immeasurable valuable.

Thus, the observation of the modification of a particular part of a physiological system (leaving the rest of the system intact) on drug effect can go a long ways in identifying mechanism of action and indicating further avenues of improving drug effect.

10. "A Pharmacology Primer" features full-color illustrations and new examples to aid understanding. How important is visual representation in conveying complex pharmacological concepts, and what approach did you take to ensure clarity and comprehension for readers?

The depiction of complicated schemes visually is critically important to the understanding of pharmacologic effect on physiology. Oftentimes a drug will affect numerous parts of a system and it is important to see the array of outcomes in a concerted way; diagrams and flowcharts can do that.

One of the most versatile and important tools in pharmacology is the ‘dose response’ curve which functions as compact statement about drug action, potency and efficacy; variation in dose-response curves thus becomes a universal language for expressing drug effect.

11. The reorganization of content for better flow and clarity in this edition is a notable feature. What motivated these changes, and how do they enhance the reader's learning experience?

Such reorganizations basically reflect changing technology and emphasis in drug discovery as new techniques yield new information. Twenty years ago, the cutting edge may have been robot highthroughput screening whereas now genomics, structural biology and virtual screening have taken the fore.

Hopefully, this book will reflect the changing times in discovery and guide readers who may not have the time to keep up with then changes. In addition, the new ideas presented are put into historical perspective where readers can see their development and from that, also see their potential.

12. As a professor at the University Of North Carolina School Of Medicine, how do you integrate the principles and techniques from your book into your teaching and research?

In years past, there was a student perception that scholarly activity could only be pursued in an academic environment and thus pharmacology and drug discovery took a secondary career choice role.

Now it is  realized that industrial drug discovery is every bit as academically challenging and rewarding; drugs do not automatically appear from screening and industrial pharmacologists need to be practicing scientists in the pharmacologic community at the cutting edge to apply new knowledge to the discovery process.

Moreover, the face of drug discovery has changed and now it is pursued in academia with equal vigor as it is in in industry. At UNC we offer specific courses in drug discovery to expose students to careers in discovery utilizing pharmacology since this, to a large extent, is where the new opportunities lie. Such courses are increasingly being developed in other universities as well.

13. Given the rapid pace of change in pharmacology and drug discovery, what advice would you give to students and early-career researchers entering this field?

I tell students to imagine the ‘pure’ sciences such as genetics, chemistry, physiology, biochemistry as purebred dogs; in this setting, a pharmacologist would be represented by the greatest cross-bred mix (‘mutt’ if you will) since we take from all of these disciplines towards a single pursuit, the chemical control of physiology.

So I council students to ‘think big’ and see the big picture of utilizing all of the sciences toward the discovery of new therapies. Given this, they should not hang their star on the latest fashionable technology but rather incorporate what it brings to the field and then think how it can be extended.

14. Lastly, what are your hopes for the future of pharmacology and drug discovery, and how do you envision your book contributing to the ongoing advancements in this critical field?

The expansion of understanding of physiological systems and pathological processes has been, and still is, remarkable. Even as little as twenty years ago it would not have been imagined that we would have the means to manipulate systems chemically in the way we do so today.

Given this, the horizon is very bright indeed for new drug discovery and this book is privileged and honored to be riding that train; there will always be a need for revision as the field never stops progressing.

--Issue 04--