A short thread on de novo hit generation in small molecule drug discovery

I’m lucky enough to see first hand 10+ programs a year against different, mostly novel, targets - and there are some clear trends emerging about the best approaches

1/n The more is see the output of DEL (DNA-encoded library) screens the less impressed I am - in fact, I’m reaching the point where I may never go another one… at least with current technology

Why? The sheer size and lack of drug-likeness of the hits

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Interesting reading some of the reaction to $NGM - despite the superficially sensible MoA, it never seemed likely an anti-C3 would work in GA...

Why not? After all, genetic variation that reduces function of the C3 inhibitor CFH is a causative factor in GA…

1/n And the $APLS C3 inhibitor Empaveli pegcetacoplan had its NDA accepted by FDA earlier this year, although it wasnt as effective as some had hoped

The devil is in the detail: complement activation in GA occurs predominantly in Bruch’s Membrane - a tough place to get access

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Diseases of ageing are quite distinct from conventional diseases with a genetic basis - revealsed by the incidence profile with age #MethuselahHealth Diseases of ageing occur because the machine wears out rather than because one of the components was faulty. Ageing is a property of the system not its parts…

EVERYONE ages, no matter what your genome!

#MethuselahHealth

I agree. Complement misregulation is key to understanding #covid19 symptomatic variations

https://twitter.com/cgfran01/status/1250117112535887874

This chimes with our work at #MethuselahHealth - where we have uncovered complement regulation as a key player in ageing. Around 50yo we see significant “innate autoimmunity” as proteome errors accumulate and trigger self-recognition

This is interesting. The provocative part is not the data, nor as most of the rep;ones in this thread focus on, estimates of CFR but the striking difference between US and Europe

Important to spend some time thinking about the origin of the difference

https://twitter.com/vprasadmdmph/status/1248056240581693440

The proportion of deaths that are people <65 is almost 10x higher in NYC than European epicenters. But this raw figure doesn’t correct for the age distribution of the whole population - New Yorkers likely much younger on average than citizens of Lombardy

@JohnOspanov Ok. So time for some more speculation on where we are in the #COVID19 epidemic in UK. Yes, what follows is my OPINION so don’t waste your time telling me I’m wrong - because none of us know

1/n @JohnOspanov My guess is that when random sample serology is reported for the UK we will have 5-10% antibody positive (5% if you did it now, 10% if you wait til next weekend)

That will also reflect some geographic variability with some area below 1% and others above 20%

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This is interesting (to me at least) because it’s an effect we predicted almost 20 years ago now

Following thread explains exactly why this is what you’d expect

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(H/T @manal_mehta)

https://twitter.com/johnnosta/status/1240392418366717956

ABO blood groups are caused by different sugar groups that decorate the outside of your red blood cells. A and B have extra sugars (called fucose) on them, which are missing in group O

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I do think healthcare professionals need to be particularly careful. It seems clear that severe symptoms result from high viral load. If the virus gets to very high copy number before your adaptive immune response kicks in you are at very high risk if ARDS

1/n If you are healthy & immunocompetant, then a major determinant of the outcome if that race will be initial exposure. If I am infected by 1cparticle, it takes 10 doubling times to get to 1000 particles - if I’m infected by 1000 particles simultaneously I’m there in zero time

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