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Too Many Papers

If you do a search in PubMed for the words “Cov-2 main protease screen inhibitors”, you get 295 hits. That’s as of this morning, of course – there will be more as time goes on. That represents a great deal of work done in a relatively short time (all of the citations, naturally, are from 2020 and 2021). But allow me to express what might be (for some) an annoying or unpopular opinion: that’s far, far too many papers.

Scrolling through the list will, I believe, illustrate some of the reasons I say this. To start with, there are a great many screens of approved drugs: a search for the words “Cov-2 main protease screen inhibitors repurposing” gives you 96 papers, and the similar search of “Cov-2 main protease screen inhibitors approved” gives you 94, which is surely an almost complete overlap. My hope at first was that many of these would turn out to be reviews or brief front-of-the-journal notices to full papers themselves, but that doesn’t seem to be the case. It’s just one study after another. So as designated Pain In the Rear, I have to ask if we needed over ninety different papers screening what in many cases is more or less the same set of compounds, over and over and over.

Now, some of the 96 papers make that list because they mention repurposing of approved drugs in passing, before turning to something else – generally natural products, from what I can see. My strong impression is that there are many groups who have previously described compounds from Root X or Fungus Y, and who then turned around and ran an in silico screen with these structures to see if they might dock into the main protease binding site. Very few of them actually report experimental data from a physical screen. A quick look showed that at least 79 of the 96 papers appear to be completely computational – virtual screening, docking, and so on. I have not done a similar analysis of the 295 papers mentioned above, but spot checking indicates a roughly similar proportion.

That shouldn’t be too surprising. Computational studies are a lot easier to get off the ground than a physical assay (that’s one of the appealing things about them). But that’s one of their main disadvantages as well, and I think the current state of the coronavirus protease literature illustrates that. Frankly, very few of these papers seem to me to be worth very much, and they’re worth even less with so many other broadly similar studies out there at the same time. And I don’t want to sound like I’m just picking on the in silico papers – many of the ones that did actual protease assays haven’t added too much to our knowledge, either, since (as mentioned) they often are screening pretty similar libraries. Knowing that some polyphenolic phytochemical is a high-micromolar binder to the main protease does not shorten this pandemic nor will it shorten future ones, and hearing about it several times doesn’t change that.

In sum, the majority of these papers seem to be opportunistic efforts that have jumped on the pandemic as a way to pad everyone’s list of publications. And no, I’m not surprised to see this – it’s just what one would have expected. But that doesn’t make it pleasant to watch. If you move out of the coronavirus main protease screening literature, there are untold masses of papers that might as well be titled “Stuff We’ve Already Done, Now With a Coronavirus Angle Glued Onto It So It Can Be Published Again”. No doubt some of these authors felt that they were making a real contribution, if we’re going allow intent as a mitigating factor, but I’m also sure that many others just saw a chance to publish some easy papers, and likely in better venues than usual while the editorial standards were temporarily lowered.

I should make clear that I of course don’t have any problem with people studying inhibitors of coronavirus proteases. But it should also be clear that any work like this is being stored up for the future. It was and is extremely unlikely to have any effect on the course of the current pandemic, given the amount of time it takes for small-molecule drug development. These are not vaccines, where the massive machinery of the immune system is waiting for you to set it off in the right way and where we already know a number of methods that can be put to the test in the clinic. Protease inhibitors for a new pathogen start at the bottom and have to work their way up, and it’s a long haul. Frankly, even after those years of work, the finely tuned inhibitor of the current viral protease that would come out of such efforts is extremely unlikely to be useful against future viruses. Every protease is different, and a really effective drug is going to have to take advantages of all those individual features of its target – which makes it correspondingly less likely to be repurposed. The successful antiviral protease inhibitors have been developed against pathogens that just hung there in the sky like baleful stars for years because they were hard to work up a vaccine against: HIV, hepatitis C.

Enough grumbling for one day. There’s a bright side to the way the scientific literature has worked during the pandemic – in addition to all the repetitious junk, there have been huge amounts of actual useful information that have been shared with a speed and thoroughness never seen before. That cheers me up a great deal and gives me hope that it makes us all the more ready for future emergencies. But that doesn’t mean that we should give the junk a pass. Wastes of time and effort are still wastes. On that topic, though, the situation with the number of clinical trials run during the pandemic is an even bigger disgrace, and that deserves a separate look. We really don’t want to to that again. . .

45 comments on “Too Many Papers”

  1. Harvey 6'3.5" says:

    I doubt most of the authors intentionally were “opportunistic” just to publish a paper. Instead, it was natural to turn to address covid in this emergency (as Isaacson’s biography of Doudna notes, she did as well). And there is a benefit of being able to see replication studies in real time, showing whether particular inhibitors make any sense or not.

    But it does make it hard for the reader trying to pan out golden nuggets of information from the stream.

    1. T says:

      I’m afraid I don’t share your doubt. Until recently I was an editor for a top journal and many authors were clearly just shoehorning COVID into their work in any way possible to try to get a higher impact publication than they would normally be able to aspire to? Why do I think this? Because much of the “COVID research” submitted was really really weak; stuff that anyone with scientific training would know wasn’t contributing anything useful. Many were groups that had no actual expertise in viruses or drug development and were just doing the easiest most obvious COVID-related experiments they could think of (often badly) without even bothering to check whether that ground had already been covered (by actual experts). So either these people were trying to take advantage of the pandemic for their own gain or they are idiots who don’t know the first thing about carrying out good-quality research. I’m not sure which is more depressing.

  2. Andrew says:

    Not papers of opportunity, papers of NECESSITY. Rightly or wrongly (okay, definitely wrongly), academia only works with publishing, the more the better.

    Our lab (and I suspect many others) was forced to shut down or operate at diminished capacity for almost a year. We also experienced pandemic related logjams with supplies and reagents. We even donated our glove inventory to the hospital! The university allowed us to resume lab activities for COVID related work, so of course our PI found our particular angle and pivoted. Labs that can do computational work can also work safely from home. So otherwise idle resources were funneled into mostly worthless computational and “my hammer to your nail” papers, as you found.

    1. Mantis Toboggan says:

      Agree totally that the nature of what work was allowed to resume contributed. You could work on some kind of diagnostic or protease inhibitor screening regardless of whether or not it had any chance whatsoever to impact the pandemic.

  3. Peter Kenny says:

    I think the language of many purely computational papers is inappropriate. It is asserted that a simulation ‘reveals’ something (as opposed to ‘suggests’). It is stated that ligand ‘binds’ to the target and a docking score (quoted with calorie precision) is presented as its ‘affinity’. To be fair, the difficulty in distinguishing fact from opinion in drug discovery was getting more acute even before COVID19 opened the flood gates. I’ve linked a post on drug repurposing as the URL for this comment (which celebrates former Indian PM Morarji Desai who, whatever you may think of his unorthodox approach to self-medication, lived to be 99):

    ” I sometimes wonder what percentage of the pharmacopoeia will have been proposed for repurposing for the treatment of COVID19 by the end of 2020. In particular, I worry about the long-term, psychological effects on bloggers such as Derek who is forced to play whack-a-mole with hydroxychloroquine repurposing studies.”

    1. Derek Lowe says:

      Oh yes indeed. Even while I was looking through the papers to see how many were computational, I had to look further into some of them to make sure that they were indeed in silico, because they talked so confidently about ligands and affinities in the title or abstract. . .

      1. Chemist…sometimes says:

        In my experience, a lot of comp chemists assume their calculations mean the compounds will be good 😀

        1. tally ho says:

          True – and in my experience a lot of med chemists assume compounds that they design will be good, and then forget about it when the designs turn out to be duds. For further insight into the pragmatics and psychology of drug discovery and momentum publishing, I recommend analysis of human behavior and decision making by Tversky and Kahneman:

          https://www.newyorker.com/books/page-turner/the-two-friends-who-changed-how-we-think-about-how-we-think

        2. ye74992 says:

          As a journal editor, I feel I have been like Horatio at the bridge fighting back the hordes of such papers. The conflation of docking scores with binding affinity, the soupcon of MD to make it more acceptable, the misapplied ADME scores, before the coup de grace – it’s a polyphenol! I have had to read >50 such submissions, so you didn’t have to.

          1. steve says:

            The whole drug repurposing effort is a canard. Take ivermectin. The original paper found it was active in vitro at 5uM. Maybe a lead but what pharma company would take a 5uM compound to clinical? Especially when its Cmax is 0.28uM? But that was enough for a bunch of doctors to give their patients a worming agent for a virus. Then it turns out that the big study everyone claimed “proved” that it works was fraudulent. Hydroxycholoroqine redux.. Maybe you need to add some zinc to your ivermectin?

          2. Chemist…sometimes says:

            Especially in academia (not all), there’s a negligence of understanding what goes into developing a drug and what represents a good lead. Docking scores shouldn’t really be used for any form of scientific discourse, unless someone makes the compound and tests it! … even still, the score means nothing

          3. Free Radical says:

            Steve I can’t let this slide. Remdesivir has saved lives. Maybe not as many as we’d all like, but some. No one knew at the start what might hit.

  4. Not-an-epidemiologist says:

    “Stuff We’ve Already Done, Now With a Coronavirus Angle Glued Onto It So It Can Be Published Again”

    Yep 🙁 A lot of researchers, as always, followed the money (and the KPIs). I completely agree that so much useless crap is being published right now, and it’s incredibly depressing. And some journals (oh, hi, Nature and NEJM) have clearly lowered the editorial acceptance bar if covid is dangled in front of their face. (This was maybe understandable last year; this year, though, it feels as if they’re blindly following their own precedent, and the novelty of some of their recent stuff is wearing thin.)

    But in a world where funding is becoming scarcer and scarcer, who’s to say that this was even the wrong thing to do? We all have staff and students who need incomes and stability; and it’s almost impossible to get funded to do the high-quality, high-risk, high-reward research that (I think?) most of us still want to do. It’s a brave lab head who ignores one of the few cash cows that comes their way.

    (Disclaimer — I’ve not jumped on the covid gravy train; but I can’t honestly say that I wouldn’t have if I could have.)

    1. Bru says:

      People have been talking about funding becoming scarcer and scarcer since the 1970s.

      1. Kamil says:

        And while one may dispute whether funding decreased or increased in absolute / relative terms, this does not change the fact that, relative to the importance of medical research, we are being treated like dirt. So it is not a surprise that researchers always fear for their scientific future.

        If a quick perusal of the literatures does not deceive me US funding is up in absolute terms but “Federal R&D spending has fallen about 70% as a percentage of the Federal budget” since the 70s, whereas, at least recently over the last 20 years “Gross domestic spending on R&D” across the OECD has increased marginally from 2 to 2.4% of GDP.

        1. Vader says:

          The interesting thing about the 1970s as a baseline is that this was the time of Nixon’s War on Cancer.

          Cancer won.

          I have an old friend who used to work for government who likes to say, “Any problem that can be solved merely by throwing gobs of money at it was never much of a problem.”

          Basing our evaluation of whether we’re spending enough on research on gross funding levels is pretty meaningless.

        2. Jan Veenstra says:

          (1) The number of PhD’s in the seventies was so much lower, meaning that per person there was much more money available. (2) There is what I like to call the scientific-industrial complex that on the one hand provides nice tools, but that on the other hand are expensive, in part because there are monopolies built on research originally funded by the tax payer.

  5. TPO says:

    Does anyone find PubMed citations to “front-of-the-journal notices” anything but a time-wasting annoyance?

  6. Richmond says:

    During pandemic, there’s too many people with Ph.d’s in some area like counseling or education giving Covid advice and calling themselves “Dr.”, so it looks like they are probably a medical doctor. I noticed Derek doesn’t do that … such modesty should be rewarded. Congrats!

  7. David says:

    The phenomena is not unique to biology. In about 2015, the particle physicists at the LHC thought they saw an excess of photons at 750 GEV. Theorists jumped on the observation and produced >500 papers in under a year, explaining where the excess came from in terms of fancy new physics theories. The excess later turned out to be an observational fluke, and all of those papers were worthless. (the wikipedia article on the “750 GEV diphoton excess” is a good summary). As Derek hints, there are a lot of people with time on their hands and a need to publish something – anything – to pad out their CVs.

    I, on the other hand, only publish the best stuff.

    1. Koss says:

      Sadly, if the funding agencies you depend on mostly score based on the number of papers published and the impact factor of the journals, only the best of the best can afford to publish some cheap shots.

      1. Koss says:

        I meant “can afford to never publish some cheap shots”

  8. wschow says:

    fair critique
    best when in silico/molecular modeling studies are backed up by in vitro work and also based on clinical studies/results (in other indications)
    see brilacidin / pmx 30063
    compelling in vitro results, now in ph 2 testing against COVID
    a de novo defensin-mimetic small molecule with pleiotropic properties developed by two nat’l academy of science members
    its antiviral MOA (disrupting viral integrity, blocking viral entry) suggest variants won’t affect
    in more serious disease, thought is that the anti-inflammatory will most come into play
    here’s hoping it can help w the pandemic

    Mall R, Elbasir A, Almeer H, Islam Z, Kolatkar PR, et al. (2021) A Modelling Framework for Embedding-based Predictions for Compound-Viral Protein Activity. Bioinformatics. 2021 Feb 26; btab130.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163000/

    Cavasotto CN, Di Fillipp JI (2021) In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Consensus Ranking. Mol Inform. 2021 Jan;40(1):e2000115.
    https://onlinelibrary.wiley.com/doi/10.1002/minf.202000115

    1. In vivo veritas says:

      Entry inhibition or poster boy for lysosomal disruption?

      1. drsnowboard says:

        Clinical trial in already hospitalised patients , iv, for COVID? Personally, I don’t think that has much chance of affecting the viral load phase ie early COVID. Doesn’t look like the most orally available, lung targeted molecule in the world…

        1. wschow says:

          entry inhibitor, with MOA tbd — showing virucidal and blocking properties
          more can be found here on antiviral properties – should be developed as a prophylactic to leverage its direct antiviral profile imo, or perhaps subcutaneous if bioavailable
          https://www.mdpi.com/1999-4915/13/2/271/htm
          the company has released data it seems variant-agnostic w pan-corona potential, perhaps extending into other viruses (alpha, bunya)
          in hospitalized COVID-19 patients, it’s the immunomodulatory/anti-inflammatory that are expected to be most helpful — via PDE4, inhibits various cytokines (Il-6, Il-1b, tnf-a)
          here’s hoping — marshalling innate immunity, per commentary below
          https://www.americanpharmaceuticalreview.com/Featured-Articles/576964-Significance-of-Innate-Immunity-in-Mitigating-SARS-CoV-2-Infection/
          is one to keep an eye on given the dearth of effective tx w COVID not going anywhere

          1. drsnowboard says:

            Everything that you said there screams weak non-specific activity.
            Multiple unknown mechanisms, both antiviral AND anti-inflammatory, for a molecule that looks like the equivalent of a sticky blanket. By all means trial it , but i won’t be investing.

  9. SAS says:

    How about those flavivurus NS2B-NS3 protease inhibitors, any of them make it into clinic? I remember a few non-competitive inhibitors looking kinda interesting in some in vitro and cell assays…

  10. Paul Brookes says:

    Worst example I’ve seen so far was a paper I rejected as board member for a journal. The gist of it was as follows… “I looked at the sequence of S-Cov2 and I think there’s a cryptic new gene in there, based on some overlap with other examples of that gene. People should really look into this because it could be an important target”. That was it, pure blatant speculation and opportunism, no data, no experiments, just half an hour of playing with blastp. Ugh!

    1. Anonymous says:

      Serious question, without knowing the true value of this particular example. Is there a forum for these types of “papers”? A generous interpretation might be that the author was presenting a reasoned idea for critique, the kind of thing that might be discussed among colleagues or in a group meeting and then followed up to a certain extent. In this day and age, is there a place online to talk about this kind of thing?

  11. Kevin says:

    My “favorite” in silico “result” came from a grant application my lab’s then-PI reviewed a number of years ago, for a major federal funding agency. The work presented beautiful, detailed renderings of antibody-antigen complexes. Lots of discussion of thermodynamics, and comparisons between different binding partners, and so forth.

    The only issue was that every single antigen had been docked to the hinge region of the IgG.

    1. Jan Veenstra says:

      This is really funny !

  12. J Curwen says:

    Another one of this too many papers:
    “Spike-antibody waning after second dose of BNT162b2 or ChAdOx1”
    https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01642-1/fulltext
    Seems there are almost no antibodys left after 70 days if you got AZ.
    Could explain UK & Delta.

    1. stewart says:

      The UK still has large unvaccinated populations, so we’ve got to look at the case rates in vaccinated and unvaccinated populations, rather than leap to the conclusion that the 3rd wave is driven by breakthrough infections.

      At the moment case rates are too high to easily identify clusters from the coronavirus.data.gov.uk map, but at the start of July there were large clusters in universities. There were also some clusters in schools.

      Case rates are currently falling in Scotland, but rising in England, Wales and Northern Ireland. I’m not aware of significant distinctions in public health measures (vaccination rate is a trifle higher in Scotland), so I’m wondering whether it’s down to different dates for the end of the school year.

  13. tally ho says:

    For computer-aided design that helped get an asset to the clinic, any word yet on the efficacy of Pfizer’s 3CL protease inhibitor, PF-07321332? Given the time course of SARS-CoV-2 infection and the resulting immune response, PF-07321332 may not be particularly good at mitigating mid to late-stage symptoms of COVID-19, but may have utility preventing infection onset (used as prophylactic if exposed, or first signs of infection). It’s still unclear if anti-vaxxers would be willing to take a pill instead of a vaccine as a preventative, and assuming PF-07321332 has utility, how it would be used vs. stockpiled (tamiflu).

  14. steve says:

    The whole drug repurposing effort is a canard. Take ivermectin. The original paper found it was active in vitro at 5uM. Maybe a lead but what pharma company would take a 5uM compound to clinical? Especially when its Cmax is 0.28uM? But that was enough for a bunch of doctors to give their patients a worming agent for a virus. Then it turns out that the big study everyone claimed “proved” that it works was fraudulent. Hydroxycholoroqine redux.. Maybe you need to add some zinc to your ivermectin?

  15. Free Radical says:

    “… Every protease is different…”

    So Derek hasn’t looked at the homology of CoV-1 Mpro vs. CoV-2 Mpro.

    (Super huge fan and multi decade reader of the blog, and I get the overall point, just makin’ an observation.)

  16. Wim says:

    I do quite a bit of docking and I often have to give a reality check to some of the collaborators. Many are surprised to hear that it is not only and imperfect technique but that there is only a very weak correlation between a docking score and a binding energy or other type of real measured affinity. However, for certain well behaved systems docking can be quite powerful for predicting binding poses, and is nice as an adjunct to analog design, checking what makes sense sterically, how thing are organized in 3d, and can be effectively very helpful as one component in a greater drug design effort. Personally, I would never publish a paper with just docking values. Unless it would be a paper where the focus is a novel docking method, but in such a case you would want to compare your docking performance with previously measured data anyway and not on unknown data.
    I was likewise especially annoyed to see so many preprints where researchers to a virtual screen of their favorite NP libraries and that’s it. This significantly decreased the signal to noise data of some of these servers. I actually did a bit of playing around with the cov2 main protease and related proteases, and it is a fun to work with, seemingly well behaved system but I didn’t even consider publishing anything before getting compounds made and tested. As some others have suggested, I think a “generalist” protease inhibitor is not necessarily such an outrageous idea, for example see this paper https://pubmed.ncbi.nlm.nih.gov/27027316/

  17. Jay says:

    Hi Derek, I just wonder if you could comment on Andrographolide. Its source Andrographis paniculata is being pushed hard as a COVID cure in Thailand. It is pretty sad as there is no good data to back it up. Not a lot of interesting paper so far but some suggests inhibition of the proteases a cysteine Michael-addition to the alpha, beta unsaturated lactone. Is not that to be expected of such PAIN compounds? Or do you think it could be selective? What is your perspective as a chemist?

  18. Bob Clark says:

    Would it be an overstatement or an understatement to say we are in the midst of an epidemic of unuseful COVID-19 papers?

    1. sgcox says:

      What do you mean unuseful ?
      It unquestionably helped many scientists to beef up their carriers with highly valuable Nature/Science/Cell/Lancet/NEJM/etc. papers and opened new ways to secure so needed funding.
      You are simply too cynical and negative !

  19. Julian R says:

    “Knowing that some polyphenolic phytochemical is a high-micromolar binder to the main protease does not shorten this pandemic”

    But why not?
    Is it simply because drug development takes ages? That’s not really the fault of the people running computational studies (irrespective of how flawed or redundant those papers might be)

    1. Derek Lowe says:

      It’s because polyphenols tend to have very poor behavior in vivo, and because high micromolar potency is almot invariably too weak to be effective against such targets.

      1. Lane Simonian says:

        Almost invariably is a good description because it does not mean always.

        Many phytochemicals inhibit viruses all the way up to human beings and then they fail. However, a few may work in human beings. Panax ginseng/Korean red ginseng which combines saponins, methoxyphenols, and polysaccharides may be a good example of the latter.

        Preventive Effect of Korean Red Ginseng for Acute Respiratory Illness: A Randomized and Double-Blind Clinical Trial

        The study suggests that KRG may be effective in protecting subjects from contracting ARI, and may have the tendency to decrease the duration and scores of ARI symptoms.

        https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3524425/

        In addition to potential anti-viral activity, panax ginseng is likely reducing the oxidative and inflammatory effects of the virus itself.

        In the case of the Novavax vaccine, the saponins from the Chilean soapbox tree may not only be acting as an adjuvant (which reduces the level of spike proteins needed to produce immunity), it may be limiting the oxidative stress and inflammation caused by the coronavirus. Therefore one would expect that it would reduce, perhaps even eliminate rare autoimmune reactions to the vaccine.

        Finally, I will throw this one in for saponins for neurodegenerative disease (although methoxyphenols likely do the same, only better).

        “Saponins, an important group of bioactive plant natural products, are glycosides of triterpenoid or steroidal aglycones. Their diverse biological activities are ascribed to their different structures. Saponins have long been recognized as key ingredients in traditional Chinese medicine. Accumulated evidence suggests that saponins have significant neuroprotective effects on attenuation of central nervous system disorders, such as stroke, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, our understanding of the mechanisms underlying the observed effects remains incomplete. Based on recently reported data from basic and clinical studies, this review highlights the proposed mechanisms of their neuroprotective function including antioxidant, modulation of neurotransmitters, anti-apoptosis, anti-inflammation, attenuating Ca(2+) influx, modulating neurotrophic factors, inhibiting tau phosphorylation, and regeneration of neural networks.”

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