Ramblings: May 2022
11 December 2022
Still catching up on Substack posts at the end of the year! Here are some collected Twitter ramblings from May 2022, with additional commentary interspersed.
This month’s photo of the month is from the Mattabesett Trail in Giuffrida Park, Meriden, CT, near the summit of Chauncey Peak. The Metacomet Ridge, which runs the length of central Connecticut from New Haven to the Massachusetts border, offers some of the finest hiking in the state outside of the Appalachian Trail corridor.
This is a “top 5 in the state” hike for me - probably one that I’ve done more than any other. It has just enough challenge, and payoff, to keep you coming back for more. My son has shown a lot more interest in coming along on trips this year, and I’m happy to oblige him.
This is the primary fallacy of ignoring the log-normal distribution as a medicinal chemist, and why I push so hard for folks to pay attention to geometric statistics. Ignorance here will lead you directly to bad decision-making based on non-significant differences. This isn’t to say that compounds with 10 nM and 30 nM IC50s can’t be different, but to really shore that up you’d need many more repeats to narrow the confidence intervals. This job is hard enough without shooting yourself in the foot too.
Fully aligned with Drug Hunter’s article here. I wrote tweetorials earlier in the year speaking to all manner of structural alerts, including carboxylic acids. My principal objection to carboxylic acids is that they’re negatively charged at both intestinal pH and blood pH, and therefore have a tough time passively crossing cell membranes. This can lead to both poor oral absorption and poor cellular uptake at the site of action. Others have become concerned with the potential reactivity (and thus toxicity) of acyl glucuronides, which are a primary metabolite of many carboxylic acid-containing drugs. But I think there’s room for nuance here. For one, I’m not aware of any studies that conclusively show acyl glucuronides to be a smoking gun for tox in a universal way. For another, we can’t discount for both permeability and tox that there are plenty of approved drugs out there featuring a carboxylic acid. If these perceived problems were universal, carboxylic acids would never make it into drugs. So like most things in medicinal chemistry, nuance is required. Do the experiments; there’s no substitute for data.
If I could time travel back to the beginning of my career and give my younger self one piece of career advice, this would be it. Drug discovery is a hard business, and the adversity one encounters along the way engenders a great deal of passion in its practitioners. If you have the grit to see a project through to nomination of a clinical candidate, you also have a mind to get pissed off at all the obstacles — technical, human, and institutional — that get thrown in your way. It took me a long time to understand that most of these obstacles are not malicious, but arose somewhere along the line from someone’s good intentions based on past experience. You’ll get a lot further by being selective about which obstacles you really need to remove, and framing some positive intent onto the ones that you choose to go after. But if you try to tear down everything, you’ll burn yourself out, and also find yourself short on friends and allies when you need them.
See previous post about the log-normal distribution. The “acceptable error” limit in a biological assay is not an exaggeration.
I’m a big fan of the movie Interstellar, and seeing these real-life composite images of black holes has been one of my science highlights of the year.
A different way to frame this, which I see all the time: sometimes it seems like project leaders are afraid to succeed. They’ve got a good thing going, but they want to run just one more experiment, discharge one more element of risk, before proceeding. This business is tough enough without the team erecting additional obstacles in its own path. Sometimes this is down to lack of confidence or experience, but it can also be an institutional fear of withering criticism from a senior leadership/management team. Smart leaders empower their project leads and spur them on to make snappy decisions — not bury them under the weight of a thousand mandates. Nothing — nothing — will frustrate a project leader more than creating arbitrary advancement criteria and moving the goalposts. It sends a clear message that you don’t trust the project leads to do their jobs. Don’t be that leader. If you find yourself doing this to teams, maybe you should check in on your own insecurities.
This is an underrated tweet. I can’t tell you how many times over the years I’ve seen someone managing something this way — from compound requesting into workflows to analysis of SAR-driving data to creating a sign-up sheet for the holiday potluck. There’s nearly always a better way than Excel.
Hard to believe it’s been 25 years since this incident. I sense that lab safety in academia has improved a lot in the interim. It’s unfortunate that it takes tragedies to move the needle though.
The number of people I know who aren’t in the pharma business who will tar and feather the entire industry because of guys like Shkreli is… a lot of people. Turing was a bottom feeder’s bottom feeder among generic companies. Most people I know who don’t get the distinction are also wholly uninterested in listening to me for long enough that I can explain the distinction. A good thing for me and anyone else in pharma to remember the next time we paint a group or industry we know nothing about with a broad brush.
To publish is human; to correct the record is divine.
I’m still eagerly awaiting some invites to speak at academic institutions. More than happy to do it. My DMs are open.
The struggle is real.
The Manhattan has become my drink of choice this year. Simple and elegant.
Sanitized med chem stories are never all that informative in the end. Pull back the curtain and show me all the stupid wrong turns and missed opportunities. That doesn’t make me think any less of you as a chemist, because I also make stupid wrong turns and miss opportunities. The real shame is that we pass on communicating the real world stuff we could all learn from to protect our precious egos.
Many posts about this topic this year. But I dislike the language of “leaving” anything. You’re moving forward, with purpose, because you’re a badass.