How can I become a great medicinal chemist? This is a review article published by Dr. Mark A. Murcko, a senior medicinal chemist, at J. Med Chem. Dr. Mark A. Murcko graduated from Yale University in the early years and successfully promoted the launch of seven drugs, including glaucoma, HIV, HCV and cystic fibrosis. He has worked for a number of pharmaceutical companies, including Merck and Vertex and is currently the founder and CSO of Relay Therapeutics. In this review article, Mark A. Murcko combines his observations and experiences, summarizing the characteristics of many great medicinal chemists have in accordance with the two categories of "general" and "professional", hoping to give aspirations to the field of medicinal chemistry.
General trait
Ÿ The general trait is more like a "successor's manual", including:
Ÿ Strong curiosity, continuous learning
Ÿ Focus on key issues
Ÿ Focus on pragmatism
Ÿ Not only value data, but also often question data
Ÿ Pay attention to details
Ÿ Full of urgency, always looking for the next breakthrough
Ÿ Realize that great scientific discoveries will appear at any time
Ÿ High savvy, often creating new technologies
Ÿ Challenge assumptions and dogmatism
Ÿ Passionate about work
Ÿ Aware of own ignorance, and know what they don't know
Ÿ Brave to face failure
Ÿ Good at communication
Ÿ Have super high emotional intelligence
Ÿ Ok to be an "unknown hero"
Ÿ Willing to learn from others and willing to guide others
People with these 16 qualities can become the best in any industry.
Professional trait
1. Always think about what features the target product needs
At the beginning of the project, great drug chemists have a clear "target product profile" (TPP), which is what the design molecules must achieve in order to be clinically meaningful. A clear TPP gives them a good feeling of deciding when a molecule is "good enough" in all respects and can move on to the next stage. They also know that TPP is related to the biological information of the target, the possible patient population, and market competition. For example, when designing a hepatitis C virus (HCV) protease inhibitor, Vertex Pharmaceuticals decided to look for a compound that preferentially distributed to the liver because it is the major site of HCV replication. Consciously optimizing the distribution of compounds to reduce drug toxicity, they eventually developed the anti-hepatitis C star drug telaprevir.
2. Pursuit of creative drug design
They often come up with new ideas, sometimes unexpectedly, and creative. For example, Merck-Frosst's cathepsin K project uses a trifluoroethylamine group as an isostere of the amide to avoid hydrolysis, allowing the compound L-873724 to be administered orally, avoiding enrichment in lysosomes, and in the Ganges The monkey bone resorption model is eye-catching.
HIV-1 protease inhibitors, by inhibiting the activity of HIV protease, cause HIV-1 to produce immature, non-infectious virus particles in infected cells, ultimately achieving the purpose of preventing the virus from assembling properly and inhibiting viral replication. In contrast to the peptidomimetic competitive inhibitors, the researchers designed a 7-membered cyclic urea structure that fits the active center of the enzyme by analyzing the crystal structure of the HIV protease and inhibitor complex. HIV protease is a homodimer composed of two peptide chains with C symmetry. Such compounds also have C symmetry, such as the compound DMP-450 (mozenavir), which just binds to the HIV protease dimer. As shown below.
In addition, there are boron-containing drugs that introduce boron into the drug design, such as bortezomib, ixazomib, and avaborole.
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