Thread by @BRAINCURES

885 of all small molecule drugs pass the rule-of-five test; of these, 619 (70%) are actually dosed orally, whereas 159 (20%) of orally dosed drugs fail at least one of the rule-of-five parameters
-John P Overington, Bissan Al-Lazikani and Andrew L Hopkins
nature.com/articles/nrd21…

@johnpoverington et al determine that all current drugs with a known mode-of-action act through 324 distinct molecular drug targets. 266 are human-genome-derived proteins, and the remainder are bacterial, viral, fungal or other pathogenic organism targets
readcube.com/articles/10.10…

Small molecule drugs modulate 248 proteins, of which 207 are targets encoded by the human genome. Oral #smallmolecule drugs target 227 molecular targets, of which 186 are human
-@johnpoverington, Bissan Al-Lazikani, Andrew Hopkins
nature.com/articles/nrd21…

https://twitter.com/braincures/status/1571831509169963008?s=21

Biological drugs target 76 proteins with marketed monoclonal antibody therapeutics acting on 15 distinct human targets. Only 9 targets are modulated by both small-molecule and biological drugs, with differing agent types usually targeting different domains
nature.com/articles/nrd21…

Polypharmacology can be rationalized by similarities of key pharmacophores in the binding sites of proteins from different families, and when comparing proteins from within the same protein family, can be rationalized by differences in the physicochemistry
nature.com/articles/nrd21…

Analysis of the gene-family distribution of targets by drug substance for both small-molecule and biological drugs reveals that more than 50% of drugs target only 4 key gene families: class I GPCRs, nuclear receptors, ligand- and voltage-gated ion channels
nature.com/articles/nrd21…

Approximately 130 privileged druggable domains’ cover all current drug targets. This number is in stark contrast to the projected number of protein families and folds (10,000 folds and more than 16,000 families) based on the SCOP & PFAM databases #biotech
nature.com/articles/nrd21…

1,620 distinct human protein sequences are linked directly to a genetic disease. Of these, 105 are drug targets, corresponding to 47% of human #drugtargets that are directly associated with a disease based on Online Mendelian Inheritance of Man database
nature.com/articles/nrd21…

Of 361 NMEs approved by the FDA, 76% targeted a precedented drugged domain & only 6% targeted a previously undrugged domain; the remainder have either unknown targets (4%) or are believed not to have distinct molecular targets underlying their action (17%)
nature.com/articles/nrd21…

The rate of target innovation is surprisingly constant over the past 20 years, with an average rate of first-against-target drugs of 5.3 new ‘drugged’ targets per year
John P. Overington, Bissan Al-Lazikani and Andrew L. Hopkins
nature.com/articles/nrd21…

The 1st approved indications for drugs acting on the new targets are commonly orphan diseases, suggesting that innovation primarily occurs at the edges of the market, whereas innovations in the major disease indications can occur as rarely as once a decade
nature.com/articles/nrd21…

It is tempting to see advances in technology as transforming the rate of innovation in discovery, but there has been little evidence of technological developments to date improving our ability to tackle new target classes with increasing speed and success
nature.com/articles/nrd21…

Incremental changes and hard-won gains in fundamental biology and chemistry, and clinical science is still state of the art. As James Black is famously quoted as saying: “the most fruitful basis for the discovery of a new drug is to start with an old drug”
nature.com/articles/nrd21…

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