design of HIV-1 protease inhibitors with x-ray crystallography

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Back in the 1980s AIDS - acquired immunodeficiency syndrome - was a very poorly understood disease. Scientists soon linked the disease to the virus HIV-1. One of the key enzymes for HIV-1 is HIV-1 protease. HIV-1 protease cleaves a viral polypeptide into various functional proteins. If you inhibit HIV-1 protease, the viral load in the patient decreases. OK, at this point, HIV-1 became a promising drug target for HIV-1 infected patients. Fortunately, a quality x-ray structure of HIV-1 protease was reported in 1989.
At this point, researchers had two options. Option 1 - Design an HIV-1 inhibitor based on the structure of the viral polypeptide. This is an example of a peptide lead. Peptide leads tend to show great on-target potency, but achieving good PK properties is hard. Peptides tend to have poor stability in the stomach, and they often fall outside of Lipinski’s rules. The second option was to start over and design a small molecule inhibitor. In either case, knowing the three-dimensional structure of HIV-1 [protease] would be helpful for improving potency and even selectivity for the target.
Let’s start with the peptide lead approach. Several drugs emerged from this approach including ritonavir, which is on this slide. The backbone of ritonavir does somewhat resemble a polypeptide. The structure has some atom replacements, additions, and substitutions to improve its stability and absorption. The structure does have two violations of Lipinski’s rules. I couldn’t find a reported oral bioavailability, but apparently it is good enough - just likely barely good enough - to achieve efficacious exposure. So, the peptide lead approach was successful. How about the small molecule approach?
Well, the small molecule approach did not fare as well. Scientists have been able to design wonderfully potent HIV-1 protease inhibitors. One example is DMP-450, which I believe advanced into clinical trials. Most of the optimization of DMP-450 was achieved through the use of cocrystals of the compound with HIV-1 protease. DMP-450 has a high molecular weight but is technically compliant with Lipinski’s rules with just the one violation. I do not have a number for DMP-450’s bioavailability. I also do not know why the compound failed to advance in the clinic, but I believe it was related to poor PK properties. Let’s see the cocrystal of DMP-450 with HIV-1 protease.
Here is the cocrystal. The drug is in dark grey. This image is quite busy, but we can get what we need from it. The dotted lines represent interactions between the drug and protease. As you can see, DMP has a wealth of interactions with the target - fantastic potency. Unfortunately, potency alone does not make a drug. The compound also must have favorable PK and good safety. In any case, knowing the target structure is certainly helpful for optimizing the potency of a compound for its target. We just can’t, however, ignore PK and safety.