Medicinal chemistry: Key to safe medicines

One of the most important issues of discovery medicinal chemistry today is the continuing need for excellent synthetic chemists, feel Dr Ramaiah Muthyala and Dr Akella Venkateswarlu

Medicinal chemistry represents the design and discovery of new compounds that are suitable for use as drugs. The discovery of a new drug is not confined to include design and synthesis, but also the development of testing methods and procedures needed to establish how a substance operates in the body and its suitability for use as a drug. Drug discovery may also require fundamental research into the biological and chemical nature of the disease state.

Medicinal chemistry attempts to provide a framework for a variety of topics. In other words, a medicinal chemist has his/her own language—therapeutic index, hits, leads, SAR, QSAR, logP, receptors, ligands, pharmacophore, toxicophore, therapeutic window, pharmacokinetic and pharmacodynamics etc—which is foreign or less familiar, to most pure synthetic organic chemists.

In recent years, new scientific advancements in synthetic methodologies and novel technologies have revolutionised the practice of synthetic organic chemistry.

Drug design has received a big boost from disciplines such as combinatorial chemistry, automated synthesis and compound purification and identification. In addition, with the introduction of high-throughput screening, many targets are being assayed and many hits being evaluated simultaneously.

However, success in this arena still requires skilled medicinal chemists who make correct choices about which ‘hits’ are likely to play out as true ‘lead’ structures. These choices are often made with insights gleaned from interactions with computational chemists, structural biologists and a host of other disciplines. Even though the lead structure will have a long road ahead, it is expected that on the way it will meet a plethora of hurdles to survive to become a successful drug.

Those who are most proficient with computational tools have the advantage of delivering new drug candidates more quickly and at lower cost than their competitors. The systematic use of a wide range of computational tools facilitates and enhances the drug discovery process. Many tools are available. For example 2D or 3D library screening for lead compounds, predicting the properties of drug-like molecule, docking experiments, virtual screening etc. The synthetic chemists and medicinal chemists should be familiar with all these tools.

New technologies

Many new technologies such as rapid analog synthesis, open access liquid chromatography, mass spectrometry and high speed automated high-performance liquid chromatography etc are now facilitating medicinal chemists. Their main aim has been to shorten the cycle time of synthetic operations. Because of the rapid synthetic cycle times, a medium-sized group of medicinal chemists can now advance several different lead classes at the same time and thus potentially shortening the time-lines for developing a hit or lead into a true drug candidate.

Usually, it is not clear at the start of a project what the downstream toxicological, metabolic or off-target liabilities of a particular lead class are likely to be; so different structural classes should be investigated simultaneously for data-driven decisions.

The nature and quality of the starting hit or lead compound would determine the progress of the discovery programmes. Our preference, like most other experienced medicinal chemists, would be to start in a structural series that has inherently good ADME properties, albeit with acceptable potency on the target receptor, and then set about improving the potency on the druggable target.

However, working in the other direction, ie. starting with a potent molecule that requires modification to optimise ADME and toxicological properties, against opposing structural parameters within the predefined tight structure-activity boundaries required for potency, is also practiced widely.

Institutional knowledge

Some institutions have a long history of drug discovery. New information can be guided by the institutional knowledge. India is just developing such capabilities. The drug discovery experience of pharmaceutical companies should be recognised, captured and then passed on to the young scientists or next generation. Companies that accomplish this—for example, holding in-house workshops on drug design and lecture series on medicinal chemistry—will help to teach the next generation of scientists the art of successful drug discovery. It is like a relay race.

The biomedical research carried out by pharmaceutical companies still represents only a small percentage of the overall worldwide research effort on diseases and approaches to their treatment. Academic and government labs funded with public monies often provide much basic research and fundamental insight that can direct researchers toward novel ways of attacking diseases. Pharmaceutical companies quite often sponsor such projects for their benefit at much lesser cost than conducting the research by themselves at their facilities.

Synthetic chemists

One of the most important issues of discovery medicinal chemistry today is the continuing need for excellent synthetic chemists. The recent advances discussed above have put more tools in the chemist’s toolkit, but in order to use these tools effectively, it invariably comes down to the ability of medicinal chemist to make the ‘correct’ molecule in a timely and cost-effective manner.

Central Drug Research Institute (CDRI) Lucknow, whose mission is to strengthen and to advance the field of drug research, is one of the first and few laboratories that was established in India. Its commitment is to establish multifaceted infrastructure for drug R&D. Research activities of CDRI are aimed at developing drugs, diagnostics and vaccines relevant to Indian climates. In addition NCL, Poona, IICT, Hyderabad and other CSIR labs, we mention NIPER, Chandigarh, UDCT, Mumbai and PERD, Ahmedabad for their contributions to teaching and research in areas relating to drug discovery and development.

Today, medicinal chemists who are engaged in drug discovery are part of inter-disciplinary teams and must therefore understand not only the field of organic synthesis, but also a range of other disciplines to anticipate problems and interpret developments to help move the project forward. The early in vitro

screening used to guide SAR studies does not help chemists to overcome pharmacokinetic liabilities of their compounds. On the other hand, to evaluate in vivo animal models, differences in animal and human metabolism require screens be developed that are predictive of human pharmacokinetic performance.

Role of snythetic chemist

The synthetic chemist has the role of a conductor for a full orchestra—a champion in drug discovery: The conductor may not be an accomplished player of all musical instruments, but is well aware of the tunes, melodies and rhythms other artists are contributing to the over all quality of the music. As a scientist involved at the very early stages of drug discovery, including the setting of project objectives, the medicinal chemist with leadership qualities has the opportunity to act as a champion for the drug candidate throughout the long R&D process. To act as a champion for a drug candidate, preferably a chemist with current knowledge of all aspects of the drug programme, one must take an enduring, pervasive interest in all aspects of the development process, especially in helping to solve those seemingly intractable challenges that inevitably arise during the long path to regulatory approval.

Without a champion, a drug candidate can lose momentum and stall irreversibly. Medicinal chemists today live in exciting times. They are key participants in the effort to produce more selective, more effective and safer medicines to treat diseases. Arriving at a key decision requires considerable experience and sound judgment on the part of the leader, as well as the group of senior scientists collectively charged with this responsibility. Whatever the merits of the business decisions, the role of serendipity, chemical intuition and creativity in thoughtfully selecting a chemical target to synthesise, has not diminished.

Conclusion

In the modern emerging business scenario in India, there is an urgent need to train chemists whose skills are applicable to international business practices. In the current context, this responsibility invariably falls on medicinal chemists much more than others.

So the Indian pharmaceutical industry should inspire synthetic chemists to become medicinal chemists and initiate them to perform well in interdisciplinary team settings.

Dr Ramaiah Muthyala is Associate Professor, Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota;
Dr A Venkateswarlu is Technical Adviser, Dr Reddy’s Research Foundation, Hyderabad.