A recent innovation in medicinal chemistry has opened up avenues to discover medicines for diseases that we could not have imagined even just a few years ago. The lock and key analogy, conceived by the German chemist Emil Fischer over 120 years ago, is still relevant but today’s diseases require medicinal chemists to discover much smarter keys - keys that do more than simply turn off a disease-causing protein. For example, today’s oncology drug molecules need to be highly selective and powerful at the same time while modern CNS drugs need to gently modulate brain activity.
The strength of a drug’s action depends largely on how well it fits into the lock or binding site of the disease-causing protein. To design a perfectly fitting key we need to see, at the atomic level, what happens inside the lock once the key binds. That’s the principle behind structure-based drug design. Seeing, atom for atom, exactly how a potential drug candidate binds, which atoms fit perfectly and which ones do not. This enables us to discover the precision quality molecules that are demanded by today’s most significant drug targets.
There are three main approaches that can be used to “take” pictures of a broad range of proteins and protein assemblies.
1. Nuclear Magnetic Resonance (NMR) spectroscopy is mainly used for very flexible proteins or protein domains in solution with a lower size limit.
2. X-ray crystallography uses near-perfect crystals of the disease-causing protein in a more static fashion by using X-ray diffraction mainly at very low temperatures (100 K).
3. Cryo-electron microscopy (cryo-EM) is a more recent approach that utilizes powerful low-temperature microscopes to determine 3D structures of proteins and large macromolecular protein assemblies in solution.
The key fitting perfectly into its lock is just one of many criteria a drug molecule must fulfill. There are more than fifty parameters to be considered to successfully discover an effective drug. This, combined with the enormous size of chemical space (~1060 molecules), requires an iterative endeavor that leverages the joint brain power of scientists working together as a team.
Pushing back the boundaries with cutting-edge technologies in medicinal chemistry is enabling us to find molecules for targets that previously seemed undruggable with traditional approaches. And that's just the start. Approaches such as structure-based drug design, PROTACS, and AI are enabling us to effectively explore the infinite possibilities of chemical space.
References:
1. Juergen Mack, Vice-President, Medicinal Chemistry Darryl McConnell, Senior Vice President and Research Site Head, Austria, Innovation in Medicinal Chemistry: Unlocking Unsolved Diseases
https://www.boehringer-ingelheim.com/human-health/science-stories/innovation-in-medicinal-chemistry
2. Kessler, D., Bergner, A., Böttcher, J., Fischer, G., Döbel, S., Hinkel, M., Müllauer, B., Weiss-Puxbaum, A. and McConnell, D.B., 2020. Drugging all RAS isoforms in one pocket. Future Medicinal Chemistry, (0).
By Jaideep Khandekar.
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