A couple of months ago I enjoyed a visit to the US (my first for eight years) on which I caught up with old friends before and after a few days in Vermont (where a trip to the golf course can rapidly become a National Geographic Moment). One highlight of the trip was randomly meeting my friend and fellow blogger Ash Jogalekar for the first time in real life (we’ve actually known each other for about fifteen years) on the Boston T Red Line. Following a couple of nights in green and leafy Belmont, I headed for the Flatlands with an old friend from my days in Minnesota for a Larry Miller group reunion outside Chicago before delivering a short harangue on polarity at Ripon College in Wisconsin. After the harangues, we enjoyed a number of most excellent Spotted Cattle (Only in Wisconsin) in Ripon. I discovered later that one of my Instagram friends is originally from nearby Green Lake and had taken classes at Ripon College while in high school. It is indeed a small world.
The five days spent discussing computer-aided drug design (CADD) in Vermont are what I’ll be covering in this post and I think it’s worth saying something about what drugs need to do in order to function safely. First, drugs need to have significant effects on therapeutic targets without having significant effects on anti-targets such as hERG or CYPs and, given the interest in new modalities, I’ll be say “effects” rather than “affinity”, although Paul Ehrlich would have reminded us that drugs need to bind in order to exert effects. Second, drugs need to get to their targets at sufficiently high concentrations for their effects to be therapeutically significant (drug discovery scientists use the term ‘exposure’ when discussing drug concentration). Although it is sometimes believed that successful drugs simply reduce the numbers of patients suffering from symptoms it has been known from the days of Paracelsus that it is actually the dose that differentiates a drug from a poison.
Drug design is often said to be multi-objective in nature although the objectives are perhaps not as numerous as many believe (this point is discussed in the introduction section of NoLE, an article that I'd recommend to insomniacs everywhere). The first objective of drug design can be stated in terms of minimization of the concentration at which a therapeutically useful effect on the target is observed (this is typically the easiest objective to define since drug design is typically directed at specific targets). The second objective of drug design can be stated in analogous terms as maximization of the concentration at which toxic effects on the anti-targets are observed (this is a more difficult objective to define because we generally know less about the anti-targets than about the targets). The third objective of drug design is to achieve controllability of exposure (this is typically the most difficult objective to define because drug concentration is a dose-dependent, spaciotemporal quantity and intracellular concentration cannot generally be measured for drugs in vivo). Drug discovery scientists, especially those with backgrounds in computational chemistry and cheminformatics, don’t always appreciate the importance of controlling exposure and the uncertainty in intracellular concentration always makes for a good stock question for speakers and panels of experts.
I posted previously on artificial intelligence (AI) in drug design and I think it’s worth highlighting a couple of common misconceptions. The first misconception is that we just need to collect enough data and the drugs will magically condense out of the data cloud that has been generated (this belief appears to have a number of adherents in Silicon Valley). The second misconception is that drug design is merely an exercise in prediction when it should really be seen in a Design of Experiments framework. It’s also worth noting that genuinely categorical data are rare in drug design and my view is that many (most?) "global" machine learning (ML) models are actually ensembles of local models (this heretical view was expressed in a 2009 article and we were making the point that what appears to be an interpolation may actually be an extrapolation). Increasingly, ML is becoming seen as a panacea and it’s worth asking why quantitative structure activity relationship (QSAR) approaches never really made much of a splash in drug discovery.
I enjoyed catching up with old friends [ D | K | S | R/J | P/M ] as well as making some new ones [ G | B/R | L ]. However, I was disappointed that my beloved Onkel Hugo was not in attendance (I continue to be inspired by Onkel’s laser-like focus on the hydrogen bonding of the ester) and I hope that Onkel has finally forgiven me for asking (in 2008) if Austria was in Bavaria. There were many young people at the gathering in Vermont and their enthusiasm made me greatly optimistic for the future of CADD (I’m getting to the age at which it’s a relief not to be greeted with: "How nice to see you, I thought you were dead!"). Lots of energy at the posters (I learned from one that Voronoi was Ukrainian) although, if we’d been in Moscow, I’d have declined the refreshments and asked for a room on the ground floor (left photo below). Nevertheless, the bed that folded into the wall (centre and right photos below) provided plenty of potential for hotel room misadventure without the ‘helping hands’ of NKVD personnel.
It'd been four years since CADD had been discussed at this level in Vermont so it was no surprise to see COVID-19 on the agenda. The COVID-19 pandemic led to some very interesting developments including the Covid Moonshot (a very different way of doing drug discovery and one I was happy to contribute to during my 19 month sojourn in Trinidad) and, more tangibly, Nirmatrelvir (an antiviral medicine that has been used to treat COVID-19 infections since early 2022). Looking at the molecular structure of Nirmatrelvir you might have mistaken trifluoroacetyl for a protecting group but it’s actually a important feature (it appears to be beneficial from the permeability perspective). My view is that the alkane/water logP (alkane is a better model than octanol for the hydrocarbon core of a lipid bilayer) for a trifluoroacetamide is likely to be a couple of log units greater than for the corresponding acetamide.