Simulations Plus, Inc. (AMEX: SLP), a leading provider of simulation and modeling software for pharmaceutical discovery and development, unveiled a powerful new molecular design capability at the American Chemical Society national meeting in Chicago last week.
Of this new capability, Ron Creeley, vice president of marketing and sales of Simulations Plus, said: “Dr. David Miller, the software product manager for ClassPharmer and our team leader for Discovery Informatics, will explain the details below. The important point is that we have developed a very powerful method for generating new molecular structures for early discovery that we believe will provide a significant improvement to the daunting task of finding good, new drug-like molecules. By combining the new R-Table Exploder in ClassPharmer with our top-ranked ADMET Predictor software, chemists can now generate molecules with a high likelihood of hitting a target while also having acceptable ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties.”
Dr. Miller explained: “In the past, ClassPharmer was often used to examine large numbers of molecules that had actually been synthesized and run through a high throughput screen to measure activity, such as binding to a particular protein. ClassPharmer was then used to cluster the compounds into classes where, in each class, all molecules share a large common substructure. The chemist would next select a particular class that shows high activity for the target, and ClassPharmer provided the ability to generate an R-Table. The R-Table page shows the common substructure with some attachment points labeled R1, R2, R3, etc. The page also shows a spreadsheet with the first column of each row containing one of the original molecules, and with columns showing the fragments attached at each R position for that molecule. This is a common tool used by chemists.
“In the collection of molecules that were run through the high throughput screen, one molecule might have had a particular fragment at R1, another at R2, and a different one at R3. Another molecule might have had the same fragment at R1, but completely new ones at R2 and R3, and so on. Some combinations of the fragments at R1 and R2 and R3 did not exist at all.
“The R-Table Exploder creates new molecular structures that use all possible combinations of fragments that were in at least one molecule at each location. This ‘explosion’ generates new molecular structures that belong to the same high activity class generated by ClassPharmer, because all share the same common substructure.
“The importance of this approach is that the new molecules are very likely to be able to be synthesized. Predicting synthetic feasibility is difficult, but since every fragment in the explosion had already been synthesized at that position in at least one molecule, the likelihood is that the new molecules can be synthesized as well. Other methods for generating new molecules often produce structures that are extremely difficult or impossible to synthesize. By running the new molecules through our ADMET Predictor software, the chemist can also assess important physicochemical properties and potential toxicities, so most of the new molecules can usually be ruled out and the chemist can focus his attention on the small subset that are most promising.”
Walt Woltosz, chairman and chief executive officer of Simulations Plus, added: “This is an exciting new capability that we’ve been working on for a few months. It relies on the core strength of ClassPharmer to generate classes that have high structural similarity, as well as our ability to predict ADMET properties with industry-leading accuracy. We believe this will enhance the value of both ClassPharmer and ADMET Predictor in early drug discovery.”