Irrational drug design, malaria, and Alzheimer’s disease

Irrational drug design, malaria, and Alzheimer’s disease: "Irrational drug design, malaria,
and Alzheimer’s disease

by Eric Drexler on 24 May 2010

Irrational drug design (aka high-throughput screening) parallels other areas of data-driven science: it abandons the methodology of traditional hypothesis-driven science — which demands a focus on specific predictions — and pursues instead the weak and humble hypothesis that looking in a general area will find something. As I discussed here, genomics and synoptic sky surveys are classic examples.

High-throughput screening for drug discovery differs from these examples in that the areas studied are real only in an abstract sense, consisting of regions of molecular-structure-space that nature hasn’t filled. And indeed, making and testing millions of drug-like molecules often turns up interesting results, in both a practical and a scientific sense.


A few of the 1000s of new anti-malarial drug candidates.

Two papers in Nature (here and here) turned this method on malaria, finding thousands of candidate drugs, defined as molecules that inhibit the growth of malaria parasites by 80% or more at concentrations in the micromolar range. The hit rates were, respectively, ~1,100/310,000 and ~13,500/2,000,000.

Many of these candidates are unlike any now in use (different structures, different mechanisms of action) and crucially, these often evade mechanisms of resistance to existing drugs — a problem that threatens to restore malaria to its previous level of deadliness across much of Africa and South Asia.
Promise beyond malaria

In our household, small risks of malaria arise only when traveling to these regions. A footnote to the search for new malaria drugs, however, indicates the potential for finding treatments for scourges of the older populations of temperate zones: the disorders of protein hyperphosphorylation that underlie the leading dementias, including Alzheimer’s disease.

These result from imbalances in the activity of enzymes that add and remove phosphate groups to alter the activity of proteins. Kinases do the addition side of this, and they are diverse and specific. Many of the candidate drugs discovered in the studies reported in Nature are thought to work by inhibiting specific kinases in malaria organisms. Molecules with similar discrimination in modulating the activity of specific kinases in human cells could provide leverage in a treating a range of human diseases, including those that can steal the mind.

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