Scientists at the UCSF, together with colleagues at the UNC, created the largest “docking-friendly” database of molecules, based on the Readily Accessible (REAL) compounds from Enamine. Practical validation of the new database was recently published in Nature magazine, demonstrating that it is capable of identifying extremely powerful and synthetically available new hits.
A year ago, University of California San Francisco (UCSF) scientists expanded collaboration with Enamine to incorporate its Readily Available (REAL) database into a well-known free public database - ZINC.
The UCSF team has further converted Enamine’s REAL molecules into three-dimensional (3D) chemical models suitable for molecular docking, opening doors for a large scale virtual screening of hundreds of millions of drug-like molecules against biological targets of interest.
To demonstrate the power of this vast and chemically diverse new screening platform, the scientists used 3D docking to screen 99 million compounds against the AmpC, a bacterial enzyme, beta-lactamase, which is involved in antibiotic resistance, and 138 million against another target - the D4 dopamine receptor of brains cells, which was showed to be involved in psychosis and addictive behavior.
As a result, researchers identified, synthesized and screening in a lab a number of highly potent hits to both targets, including one of the most potent non-covalent inhibitors reported for AmpC, and super-active and selective partial agonists and antagonists for D4. Further analysis of the obtained hits allowed to estimate that the database contains hundreds of thousands of other active hits for those targets. All findings were published in Nature, and attracted a massive media coverage and scientific discussion.
The platform, that currently contains over a billion synthetically feasible molecules, new and not found in nature, is ready to dramatically change early drug discovery.