Medicinal Chemistry Part 3 - Answers to Questions from Soon-To-Be-Graduates

In this post, I am returning to questions asked at January's biotechnology symposium.  In particular, the final two medicinal chemistry questions are addressed.  These questions are:

• What is the impact of small protein design?
• What are the advantages/disadvantages of biologics vs small molecule drugs?

Future postings will address questions relevant to employment opportunities as well as what kinds of knowledge and experience are helpful in the biopharmaceutical industry.

What is the impact of small protein design?

Proteins are highly complex structures assembled by nature from the complement of naturally occurring amino acids.  The complexity of proteins comes not only from the structural diversity of the amino acid residues contained in the protein chain, but also from the secondary structure obtained as the protein chain folds into its biologically relevant conformation.  To this end, many academic research groups are studying how various amino acid sequences fold into the different structural motifs found within proteins and enzymes.  Additionally, many software platforms were developed to help predict how proteins fold.

With the complexity associated with amino acid sequence and secondary structure, it seemed somewhat unlikely that amino acid sequences can be designed to both fold like proteins and induce an intended biological response.  However, in 1997, at least this first part was realized.  As reported (J. Am. Chem. Soc. 2007, 129, 1532) Professor Alanna Schepartz and her group succeeded in designing a synthetic protein sequence capable of folding in much the same was as natural proteins do.  This synthetic protein was prepared from beta-amino acids as compared to naturally occurring alpha-amino acids.

While the design of therapeutically useful synthetic proteins is still a long way off, shorter peptide sequences have contributed to the arsenal of therapeutically useful structures for years.  Such peptide-based therapeutics include hematide (treating anemia), integrilin (treating acute coronary syndrome) and natrecor (treating congestive heart failure).  To this end, synthetic peptides provide valuable therapeutic agents for indications which, in many cases, have no conventional small-molecule drug alternatives.

What are the advantages/disadvantages of biologics vs small molecule drugs?

Currently, there are two classes of therapeutic agents - biologics and small molecule drugs.  Classical drug discovery efforts generally target small molecules (average molecular weight is ~500) as therapeutic agents.  These are advantageous because they are generally easy to synthesize and can be administered orally. Furthermore, small molecule drugs can be designed as either agonists or antagonists of biological processes for use against either extracellular or intracellular targets.  Unfortunately, small molecules cannot presently modulate all biological targets with the specificity and potency required for useful therapeutics.  Additionally, the lead identification and lead optimization processes can be slow for this class of drugs.

Complementary to traditional small molecule drugs is the class of therapeutics collectively referred to as biologics.  This class includes proteins, enzymes and antibodies.  Such large molecules (molecular weights range from ~10,000-50,000) are generally not suitable for oral administration and must be delivered by injection or infusion. This is inconvenient because these methods of use are generally not compatible with patient self-administration.  Like small molecule drugs, biologics are useful as either agonists or antagonists of biological processes.  However, unlike small molecules, biologics are only useful for extracellular targets. Additionally, biologics are generally highly selective and highly potent against target processes. Finally, like small molecules, lead identification and lead optimization are very slow processes.

For many years, the pharmaceutical industry focused on small molecule drugs.  With the advent of the biotechnology industry, biologics have become increasingly important as evidenced by commercial successes from companies such as Genentech, Amgen and Biogen.  Through the combined efforts of traditional drug discovery and the development of biologics, advances will continue to provide treatments for medical disorders providing improved qualities of life for all.

Green Chemistry and Drug Discovery

In my recent posts, I have been focusing on questions raised by soon-to-be graduates from life science programs.  While these posts have been well received and I still have many questions to answer, one event of the recent week warrants a brief detour.  Last week, at the San Francisco American Chemical Society meeting, I was invited to participate in a panel discussion on green chemistry and its role in industry.  This was an interesting opportunity for me because, while I am aware of and fully support the philosophies behind green chemistry, I had never reduced these philosophies to practice in the execution of my laboratory responsibilities.  When asked to serve as a panelist, I was forced to reflect on the following questions:

• Why have I not utilized green chemistry?
• What I contribute to this discussion?
• How I can incorporate green chemistry into my department?

For those of you who have never heard of green chemistry, green chemistry is defined as the design of products and processes that minimize the use and generation of hazardous substances.  This definition is supported by the 12 principles of green chemistry developed by Paul Anastas and John C. Warner.  The 12 principles are:  

1. It is better to prevent waste than to treat or clean up waste after it is formed. 
2. Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 
3. Wherever practicable, synthetic methodologies should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 
4. Chemical products should be designed to preserve efficacy of function while reducing toxicity. 
5. The use of auxiliary substances (e.g. solvents, separation agents, etc.) should be made unnecessary wherever possible and, innocuous when used. 
6. Energy requirements should be recognized for their environmental and economic impacts and should be minimized. Synthetic methods should be conducted at ambient temperature and pressure. 
7. A raw material or feedstock should be renewable rather than depleting wherever technically and economically practicable. 
8. Reduce derivatives - Unnecessary derivatization (blocking group, protection/deprotection, temporary modification) should be avoided whenever possible. 
9. Catalytic reagents (as selective as possible) are superior to stoichiometric reagents. 
10. Chemical products should be designed so that at the end of their function they do not persist in the environment and break down into innocuous degradation products. 
11. Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 
12. Substances and the form of a substance used in a chemical process should be chosen to minimize potential for chemical accidents, including releases, explosions, and fires.  

In accordance with this definition and principles, green chemistry aims to incorporate the highest efficiency reactions with generation of the least amount of waste - in most cases a very formidable challenge. However, for the commercial manufacture of medications such as Lyrica and Ibuprofen, green chemistry has led to reductions of greater than 80% of their respective toxic waste streams!  Therefore, the manufacture of pharmaceuticals is, in fact, well-suited for incorporation of environmentally friendly production processes. However, this is generally not the case for research oriented activities.

Adapting Green Chemistry to Discovery Research

One of the most intriguing areas of green chemistry involves the use of chemical reactions that conserve atoms - that is, all atoms in reactants and reagents are incorporated into the reaction product.  While, in principle, this philosophy reduces waste, in practice, such chemistry is not available in a diverse enough toolbox to allow for the synthesis of compounds with structural diversity necessary for success in drug discovery.

Compare green chemistry to the promise advertised for combinatorial chemistry.  Combinatorial chemistry utilizes polymer supports on which reactions can be executed.  However, the diversity of reactions compatible with the polymers limited the applicability of solid-phase chemistry to a subset of pharmaceutically interesting molecular scaffolds.  Thus, while combinatorial chemistry is a useful tool for some structural classes, this technique is currently not the answer to the rapid discovery of novel drug candidates.  This may, one day, change with a large enough toolbox of reactions that can be utilized on various types of polymer supports.

From another perspective, consider that the definition of green chemistry relates to the design of products that minimize the use and generation of hazardous substances.  If we, in the pharmaceutical industry, were to design our target structures with waste streams in mind, we would be limited in the types of reagents we could use and we would certainly not have access to the diversity of structures necessary to succeed.  While, at first glance, this reality might lead one to believe that green chemistry is not applicable to discovery research, the first of the 12 principles reverses that perception.  In the execution of research activities, waste is generated - the vast majority being solvent waste.  Some strategies for solvent waste reduction are:

• responsible execution of reactions utilizing minimal amounts of solvents
• non-use of environmentally toxic solvents such as carbon tetrachloride and benzene
• replacement of column chromatography with recrystallization techniques whenever possible
• using supercritical carbon dioxide as an HPLC solvent
• segregation of waste solvents and solvent recovery through distillation

Through incorporation of these techniques, coupled with efficient containment of waste streams, discovery research can be environmentally friendly. Furthermore, upon reflecting on these philosophies, I feel justified in saying that:

• I daily utilize green chemistry through maximizing reaction concentrations and minimizing solvent use.
• I routinely incorporate green chemistry into my department through efforts to minimize and contain waste streams.
• I have a great deal to contribute to this ongoing philosophy through advocacy in favor of environmentally friendly practices.

Finally, as academic groups continue to develop reactions that adhere to the 12 principles of green chemistry, such reactions will find their way into broader industrial use.