.. I am sure that many people have found instances where molecular docking results have been confirmed by molecular dynamics simulations, but nonetheless yield failures when experimental tests of binding/inhibition are performed. I am, however, having trouble finding any published papers describing such failures or disappointments. I understand these failures may be hard to publish, but any proper meta-analysis of the reliability of these methods must take into account the faiures, too. And if those are never published (or are otherwise too hard to find), meta-analysis may unwittingly be skewed in the direction of only analysing successes.
If you have any citations for such papers, please add them as a reply to this question. Thanks in advance!
EDIT: I am specifically looking for works that use docking/MD to identify potential inhibitors and (in the same paper) evaluate them experimentally and find them to be failures, rather than papers which evaluate experimentally the computational predictions made by previous papers .
A nice review on the subject of docking is here:
https://www.nature.com/articles/s41596-021-00597-z
@Adam B Shapiro That is a good review/tutorial for setting up a docking campaign, but I am rather looking for works that use docking/MD to identify potential inhibitors and (in the same paper) evaluate them experimentally and find them to be failures.
I believe it is a common observation that a high proportion of virtual hits, which are generally chosen from the highest scoring ones, are either low potency/inactive when tested, or are non-specific inhibitors (when tested for that property). So basically, any paper in which virtual screening was followed up by real measurements contains such virtual screening failures.
For that matter, high-throughput screens done in real assays turn up a high proportion of false positives and non-specific inhibitors, too. In my opinion, the important test for the value of virtual screening is whether it enriches for real and specific inhibitors as compared with screening by real assays, looking at the same set of compounds. Here are some papers on this topic.
Article Virtual screening to enrich hit lists from high-throughput s...
https://pubs.acs.org/doi/full/10.1021/ci5005465?casa_token=Sc-vKMVPltgAAAAA%3AscrNfAX_xM0aoJE0zd1v8h-k9GKmJCs-p7MTKR_FLfUu52t4KZpm-LwdQQb7kaMq0vVa32ESomXNHf8p
https://pubs.acs.org/doi/full/10.1021/acs.jmedchem.5b01974?casa_token=A5CGWNMB8YAAAAAA%3AEbsh468OgaWdB5ehEDiTkg_yGljELw64gaWUzg9X6bUjHZEPlYN8fL8K0uymFmqf__jRUGl9U4TvQDNo
Adam B Shapiro You are completely right , but what I am looking for is a little different from "experimental failures from virtual-screening through docking". I mean: experimental failures of positive results from docking that have been confirmed by molecular dynamics simulations of at least 50 ns. In my experience MD simulations remove many false positives from the docking results (usually 2/3 or more of the docking results do not yield complexes stable in MD simulations), and therefore I tend to assume that the few docking results that "survive" the MD test have good odds of experimental success. However, my difficulty in finding papers showing the three methods at the same time (docking, MD , and enzymatic inhibition) makes it too hard to have a sense of the "average" rate of success among the few "docking positives" that are confirmed by MD. I hope I have now been more succesful in explaining what I am looking for...
Yassir Boulaamane Thanks for those refs, but those are still not what I am seeking: the first one has ligands that LEAVE the site within 1.2 ns in MD simulations, and the second does not have MD at all :-( I seek examples where the ligand turns out negative in the experiment but still remains bound for >50 ns in MS simulations
Dear Pedro J Silva, you are right it is difficult to publish such as results at all. I have one example of this paper, when binding score results disagree with the experiment. Unfortunately I have to admit that discussion is not so comprehensive. Our original discussion was significantly shortened, because reviewers didn't like the original idea of the paper - discuss the reproducibility of MD results. Maybe it could be helpful.
Article Mutation Hotspot for Changing the Substrate Specificity of β...
Natalia Kulik you siad "Our original discussion was significantly shortened, because reviewers didn't like the original idea of the paper - discuss the reproducibility of MD results. Maybe it could be helpful." qould you be t liberty to mail me that original discussion? Thanks in advance!
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