Prediction of Synthetic Accessibility Based on Commercially Available Compound Databases

Abstract

A compound's synthetic accessibility (SA) is an important aspect of drug design, since in some cases computer-designed compounds cannot be synthesized. There have been several reports on SA prediction, most of which have focused on the difficulties of synthetic reactions based on retro-synthesis analyses, reaction databases and the availability of starting materials. We developed a new method of predicting SA using commercially available compound databases and molecular descriptors. SA was estimated from the probability of existence of substructures consisting of the compound in question, the number of symmetry atoms, the graph complexity, and the number of chiral centers of the compound. The probabilities of the existence of given substructures were estimated based on a compound library. The predicted SA results reproduced the expert manual assessments with a Pearson correlation coefficient of 0.56. Since our method required a compound database and not a reaction database, it should be easy to customize the prediction for compound vendors. The correlation between the sales price of approved drugs and the SA values was also examined and found to be weak. The price most likely depends on the total cost of development and other factors.

Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

“…Another problem with the structures obtained is the possible synthetic inaccessibility of these compounds. However, methods exist that can check the theoretically built structure for synthetic accessibility; [23] therefore we can still screen out compounds which could not be efficiently synthesized, thus focusing on accessible compounds in further experimental studies. We showed a use case of our new method on the example of butyrylcholinesterase inhibitors.…”

Miscellaneous Topics in Computer-Aided Drug Design: Synthetic Accessibility and GPU Computing, and Other Topics

“…Tables 3 - 6 show the correlations among human SAs reported in previous articles [7, 10, 17]. The human SAs were strongly dependent on the skill and experience of the individual chemist.…”

“…Synthetic accessibility (SA) is a well-known concept in organic chemistry, but calculation-based SA predictions have been studied only in the last 10 years [1-17]. On the other hand, researchers have been using software to predict synthetic reaction pathways since the 1960s [11, 16].…”

“…( 6 ) shows one example of an SA prediction algorithm included in the MolDesk software package [17] (URL: http://www.moldesk.com/). This routine performs the SA prediction within about 0.1 seconds for a given compound with one click manipulation.…”

“…Thus the drug price is an important factor in drug development. We examined the relationship between the sales price and SA of approved drugs in the United States and Japan (US) [17]. Of course, the price of a drug is critical to its practical adoption by patients.…”