In the spirit of those “Never eat at a place called Mom’s; never play cards with a guy called ‘Doc’” rules for living, I thought I’d propose a few for the early stages of drug discovery. There are a lot more where these came from, but here are a few that I’ve found useful.

N of 2 on the N of 1: Many of you have probably seen someone who’s had to shamefacedly withdraw their earlier talk of a big advance in a project (or talk of an equally big problem). They went back and checked, you see, and ran the experiment/assay/procedure again, and . . . well . . . as it turned out, it wasn’t quite what it looked like the first time. Now, this isn’t good, but if you see it in someone who’s never made that mistake before, you can put it down to inexperience. Wild, eye-catching results (good or bad) are mostly wrong. It’s those times when they’re right that you want to start ringing the bells or hitting the panic buttons, but you will know those times because of the way the result repeats.

But when you see someone who’s fallen into this mistake more than once, it’s time to put a little mental checkmark by their name. Label them however you want: “excitable,” “clueless,” “incautious,” or something less printable, but make a note never to be fooled by them again. Odds are they’ll go on trying to fool themselves, but you don’t have to ride along in the clown car with them. Those things don’t have much room in the back seat, anyway.

This advice works the other way, too. If you have a colleague who will only talk about results after they’ve been repeated, then put a different sort of mark down for them. There might come a day when you find that an irritating habit because you really, really need some data, but believe me, it’s worth it for never having to experience the first sort of problem.

It’s Just a Tool Compound: You hear this one come up when there’s some ugly beast that is a hit in an assay, and there’s not much else to work on. No, no, this isn’t going to be a lead, not at all — what sort of people do you think we are? This is a tool compound, the sort of thing you use to, um, validate the assays and, uh, use as a starting point for virtual screening. Things like that.

You’ll notice, though, that you never hear much of this talk when there are decent structures to work on. The excuses start being made when there’s nothing else out there, and the project starts rationalizing going home with the least attractive candidate left at the bar. OK, it has a phenol. Two phenols, fine. And yeah, that’s one of those rhodanine groups, a lot of people say bad things about them, but there sure are a lot of them out there in the literature as hits, aren’t there? And there’s the nitro group, I know that the chemists don’t like those, but we don’t have to keep it on there, do we? There are plenty of isosteres for nitro, right?

Don’t be fooled. You run a real danger of working on something that will only lead you to heartbreak. The safe way to approach these things is to publicly state — via presentations, verbally in front of the higher-ups, e-mail — that if there is nothing better to work with by [insert plausible future date here] then the project is over, done, shuffling off this mortal coil, joining the choir invisible, etc. That means that the team has to devote honest effort into finding that new chemical matter during the countdown period, not just wandering off and letting the people who can overlook the compound’s faults do whatever they want with it. They’ll put it into rats if you don’t watch them closely, and where will you be then?

I’m Sure Someone Else Checked That Out: An early research project is going to be spending a lot of its time digging through the screening results. A key part of that digging is checking the purity of the alleged hits. Everyone knows this, everyone’s heard it, and everyone has a horror story or two about the time when this step was neglected and the result was sorrow and rending of lab coats. But no one still wants to do it themselves.

One of the reasons that there are things like GLP and GMP for the later stages of drug development is to make sure that things like this are done, on schedule, reproducibly, and documented every time. There’s no FDA paperwork on early research (fortunately), but that gives people a chance to let things slide. Don’t do it. Someone’s got to do the tedious stuff — check the DMSO stock that was used for the assay. Check a fresh order of it from the archives. Check the solid, too. Take the LC/MS, take the NMR, get an elemental or a metals analysis, whatever you need. It’s mind-numbing, but you don’t want to go straight to the excitement of finding out that your lead series only works when there’s 2% copper in it. And you thought your compound was just naturally came by that delicate green tint. . .

It doesn’t have to be the same person every time, unless you’ve got someone around who enjoys that sort of thing. (And if you do, you might justifiably wonder about what they enjoy during their off hours). You can rotate the pain and farm it out to several people, but just never give in to the temptation to get around to it later.

Everything’s Fine. Really: This one is more of a cultural problem than a scientific one, and it’s worse in some organizations than in others. If you’re in the kind of shop where teams have to present regular progress reports to the higher-ups, you’ll surely have noticed a tendency for some people (and some projects) to always be working just flawlessly. Beautiful, sliding along on greased fluorocarbon rails, not a cloud in the sky ahead.

What a load. Every early program has problems, some of them potentially horrific. You don’t have dwell on all the nasty possibilities, but making the opposite mistake (dusting everything with a thick coat of powdered sugar) isn’t doing anyone any good, either. People waste time putting those sorts of presentations together, and other people waste time listening to them (or pretending to). It’s theatre, and not very good theatre, at that. What’s more, it becomes clear who the people are that resort to this habitually, and that means that even fewer people listen to what they’re saying. The real danger is when this gets done because it’s what your management wants to hear. “Please fool me” is not a useful message for section heads, directors, and VPs to be sending out. Some do, though — there’s no accounting for taste.

You may have noticed some overall themes to these: don’t fool other people, and don’t be a party to letting them do the same to you. The biggest danger, though, is closer to home. Richard Feynman was right on target when he said, “The first principle is that you must not fool yourself, and you are the easiest person to fool.”