Medicinal Chemistry Free Response Questions.

 Question 1. HIV-1 protease is an important drug target. Refer to the accompanying review – Konvalinka et al., Virology 2015 (Fig. 5, pages 408-409). Explain the strategies used by HIV-1 to evade clinically used protease inhibitors. Explain how and why these strategies are effective when interactions between the synthetic drugs and protease are always much stronger than that of interactions between protease and its natural substrate. (400 words max; 10 points)

Question 2. Aspirin inhibits cyclooxygenase-1 (COX-1) by irreversibly acetylating a serine residue at position 529. It is also well-known that residue 523, an isoleucine – is a part of active site of COX-1. In its isoform, COX-2, this residue is a valine. Explain how this information can be used to design a molecule that can selectively bind to COX-2. (300 words max; 10 points)

Question 3. Kim et al., Science 2013, reported a new class of neuraminidase inhibitors. Using this manuscript as a guide (Fig. 1, page 72), summarize which residue acts as a catalytic nucleophile. What will be the effects on binding (become weaker or stronger?) of the said inhibitor(s) if this residue was substituted with the following residues: A/S/F/K; one at a time. (400 words max; 10 points)

Question 4. Not many therapeutic molecules have been on the cover of TIME magazine. However, Gleevec (Imatinib; Novartis) has had this honor on May 2001. See this web-article to gain more information about Gleevec: https://www.nature.com/scitable/topicpage/gleevec-…. Explain why Gleevec – a tyrosine kinase inhibitor – has been such a trendsetter as a kinase inhibitor. (400 words max; 10 points)

Question 5. The nucleocapsid protein of HIV-1 is responsible for packaging the viral genome and thus represents an attractive target for anti-HIV therapies. Using the accompanying manuscript as a guide (Figures 1 and 3, Deshmukh et al., Angewandte Chemie 2018), explain the mechanism of the experimental class of nucleocapsid inhibitors called mercaptobenzamide thioesters (note: I am not looking for technical details, rather a general mechanism). Also, provide a plausible explanation as to why no clinical inhibitors of HIV-1 nucleocapsid are available on the market, despite it being an important drug target.