New Drug Discovery Tool that Can Screen More Than 11 Billion Compounds Found

Posted by beauty33 on March 31st, 2022

There are docking stations called receptors on the surface of our cells. Various compounds ranging from caffeine and dopamine to heroin, tetrahydrocannabinol (THC) and lysergic diethylamine (LSD) all bind to these receptors. Indeed, G protein-coupled receptors are the intended target of action for more than 30% of drugs currently on the market. But these drugs often also target unintended targets — imagine, blanket bombardment of the nervous system, resulting in a long list of side effects often heard at the end of drug advertisements.

Dr. Bryan L. Roth, professor of pharmacology at the University of North Carolina School of Medicine in the United States, said, \"What we need is more precise, less harmful, and equally effective treatments. But developing these better drugs is not easy. Drug developers need to know the exact chemical structure of the drug and the expected receptor in order to produce the exact chemical reaction we want within the cell. It is most important to ensure that the drug does not affect other receptors or bind to target receptors, but binding in such a way can trigger unexpected consequences in the cell.\"

\"In the past, scientists have tested molecules one by one against therapeutic targets, a long and expensive operation,\" Roth said. Therefore, scientists have constructed virtual molecular libraries and complex computer programs to test hundreds of thousands of molecules at a time. What we call \'testing\' means that a computer program searches a molecular database in which a large number of molecules can theoretically be created and can theoretically bind to a given cellular receptor with appropriate affinity. Scientists can then adjust chemical bonds in a computer program to optimize the structure of the molecule. Scientists can then actually make a small fraction of these molecules and test them in cell cultures.\"

The establishment of virtual libraries is a great leap forward in the field. Testing hundreds of thousands of possible molecules sounds like many, and some of them may have properties worth studying. However, there are billions of possible chemical combinations that could theoretically lead to the creation of nearly infinite molecules or potential drugs. As a result, scientists eventually create huge libraries of theoretical compounds: billions of mostly \'undiscovered\' and unexplored molecules, which may or may not bind to specific cellular targets; they may or may not have therapeutic value at all.

\"Unfortunately, the chemical space is huge,\" says Roth. “It is estimated that there are more chemical species in theory than there are actually molecules in the universe. Only a small fraction of potential chemicals can be physically tested.\"

Therefore, in a new study, Roth collaborated with researchers from the University of Southern California and Tohoku University to validate V-SYNTHES, a novel computational method developed by Dr. Vsevolod Katritch at the University of Southern California, allowing scientists to first determine the optimal combination of building blocks called synthon—intramolecular hypothetical units. As a seed, synthon can grow into a molecular hierarchy with the best predictive power for binding to receptor targets. The findings were published online in the Nature under the title \"Synthon-based ligand discovery in virtual libraries of over 11 billion compounds\".

\"This approach allows scientists to test billions of compounds against a therapeutic target by computational methods,\" Roth said. “To our knowledge, the largest successful computational screening to date. \"

As described in the paper, these authors tested 11 billion theoretical compounds against the cannabinoid receptor CB2, which is targeted by THC, the active ingredient of cannabis.

The Katritch laboratory developed this method and performed computational studies. With the help of Dr. Alexandros Makryannis\'s laboratory and Roth\'s laboratory at Tohoku University, they discovered a new compound, which is a highly selective and potent CB2 antagonist — a compound that inhibits or prevents receptor activity. This screening and discovery were then validated by the Makryannis lab and Roth lab. They further validated this process against another target—the kinase ROCK1.

\"V-SYNTHES represents a significant advance in the field of drug discovery,\" Roth says. It is easily scalable and adaptable, and it should open new perspectives for the discovery of potentially therapeutic chemicals for a large number of diseases, the speed of which was previously impossible to achieve.\"

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