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:…. 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. 

Expert Solution Preview


In this answer, we will be discussing the strategies used by HIV-1 to evade clinically used protease inhibitors. We will also explain how and why these strategies are effective, despite interactions between the synthetic drugs and protease being stronger than interactions between protease and its natural substrate.


HIV-1 protease is an important drug target in the treatment of HIV/AIDS. Protease inhibitors are commonly used in the treatment regimen to disrupt the viral replication cycle by inhibiting the activity of HIV-1 protease. However, HIV-1 has developed various strategies to evade the effects of these protease inhibitors.

One of the main strategies employed by HIV-1 is the development of drug-resistant mutations in the protease enzyme. These mutations occur within the active site of the enzyme and result in conformational changes that prevent the tight binding of protease inhibitors. HIV-1 has a high mutation rate due to its error-prone reverse transcriptase enzyme, which allows the virus to quickly adapt to the presence of protease inhibitors.

Another strategy involves the selection of pre-existing polymorphisms in the population. Within the population of HIV-1 viruses, there is natural genetic diversity. Some variants of HIV-1 protease naturally possess polymorphisms that confer resistance to certain protease inhibitors. When exposed to these inhibitors, these polymorphisms provide a selective advantage to the virus, allowing it to survive and replicate in the presence of the drug.

Additionally, HIV-1 protease is capable of adopting highly flexible conformations, which can influence the binding of protease inhibitors. The flexibility of the protease enzyme allows it to undergo conformational changes that can reduce the effectiveness of the inhibitors. These conformational changes can alter the shape and size of the active site, making it difficult for the inhibitors to bind tightly and inhibit the protease activity.

Despite the fact that interactions between synthetic drugs and HIV-1 protease are generally stronger than interactions between protease and its natural substrate, these strategies employed by HIV-1 are effective in evading the protease inhibitors. This can be attributed to the dynamic nature of the viral replication cycle and the high mutation rate of HIV-1. The virus is able to adapt and overcome the inhibitory effects of protease inhibitors through the generation of drug-resistant mutations and the selection of pre-existing polymorphisms. The flexibility of the protease enzyme further enhances the ability of the virus to evade the inhibitors.

In conclusion, HIV-1 has developed multiple strategies to evade clinically used protease inhibitors. These strategies include the development of drug-resistant mutations, the selection of pre-existing polymorphisms, and the flexibility of the protease enzyme. These mechanisms allow HIV-1 to overcome the inhibitory effects of protease inhibitors, despite the strong interactions between the inhibitors and the protease enzyme. Understanding these evasion strategies is crucial for the development of more effective antiretroviral therapies.

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