Confluence of Technologies Can Bring “Virtual Pharmacology” to the Next Level

One of the most popular and powerful methods of this kind is molecular docking, which has been widely used ever since the early 1980s. The idea of molecular docking is essentially to identify a perfect “key” among many diverse options, fitting to a “lock”, a biological target of choice -- using computational 3D representations of the interacting moieties.  

With all the early promise, molecular docking stumbled upon several fundamental issues, peculiar for the early decades of “digital revolution”: a lack of sufficient computing power, imperfect predictive algorithms, a limited choice of available molecules for virtual screening, and a small number of structurally characterized biological targets of sufficient pharmaceutical significance.

Last but not least, the virtual screening approach contained substantial “synthesizability risk” of not being able to physically get to all the hits, picked by a computer, in a cost-efficient and timely manner. As Asher Mullard, a freelance journalist at Nature, described it: “Many computational approaches also have an annoying habit of suggesting candidates that are nightmares to cook up in a lab.”

A lucky confluence of technologies opens doors in universe of synthesizable “hits”

Over the past several decades enormous progress has been achieved in many technologies, essential for a truly successful virtual screening effort. This finally allowed to open doors in large-scale "virtual pharmacology" of the 21st century -- with the emergence of the largest docking-friendly database of synthetically accessible compounds, outlined in a recent influential article in Nature: “Ultra-large library docking for discovering new chemotypes”.

The new virtual pharmacology platform, developed by scientists from the University of California San Francisco (UCSF) in collaboration with their colleagues from (UNC), currently contains hundreds of millions of 3D representations of novel synthetically accessible drug-like molecules, immediately suitable for large-scale docking studies, promising to change the landscape of modern hit discovery.

To illustrate the immediate practical benefit of the new “virtual pharmacology” platform, the scientists docked 99 million compounds against the AmpC, a bacterial enzyme, beta-lactamase, which is involved in antibiotic resistance, and another 138 million compounds -- against another unrelated target, the D4 dopamine receptor of brains cells, known to be involved in psychosis and addictive behavior.

The results were pretty amazing, with at least one-third of all predicted hits appearing active in subsequent laboratory validations. Scientists found a number of highly potent hits to both targets, including one of the most potent non-covalent inhibitors ever reported for AmpC, and highly active and selective partial agonists and antagonists for D4. Further extrapolation suggested presence of around half a million other potentially active hits against those targets.