SYNOPSIS:  SYNthesize and OPtimize System in Silico

Abstract

We present a de novo design program called SYNOPSIS, that includes a synthesis route for each generated molecule. SYNOPSIS designs novel molecules by starting from a database of available molecules and simulating organic synthesis steps. This way of generating molecules imposes synthetic accessibility on the molecules. In addition to a starting database, a fitness function is needed that calculates the value of a desired property for an arbitrary molecule. The values obtained from this function guide the design process in optimizing the molecules toward an optimal value of the calculated property. Two applications are described. The first uses an electric dipole moment calculation to generate molecules possessing a strong dipole moment. The second makes use of the three-dimensional structure of a viral enzyme in order to generate high affinity ligands. Twenty eight compounds designed with the program resulted in 18 synthesized and tested compounds, 10 of which showed HIV inhibitory activity in vitro.

In silico prediction of MOFs with high deliverable capacity or internal surface area

“…We ascribe this distinction to two reasons: 1) the nature of a network determines how difficult it is to grow a complicated molecule within the network; and 2) values of GSA · V SA may set an upper limit in which molecules with only a few reaction steps may already be sufficiently outstanding, as is probably the case for the pcu net. Predicted molecules with too many synthesis steps will not be attractive as practical candidates because a long synthetic route leads to low yield and high cost of synthesis 22 . We note that mean GSA · V SA for the linkers with different number of reaction steps are approximately equal, as shown in Fig.…”

“…We consider two different precursor libraries containing ∼ 50, 000 compounds each and compare their performance. We apply 84 chemical reactions that have been successfully applied in drug design 22 . Each of the predicted linkers is produced by these chemical reactions applied to the precursors, and we typically limit the number of steps in the synthetic routes to five or fewer.…”

Inhibition and substrate recognition – a computational approach applied to HIV protease

“…Nevertheless, we expect that the better accuracy of a focussed scoring function compensates the drawbacks. We have recently used a similar type of scoring function for a different target (non-competitive inhibition of HIV Reverse Transcriptase) in a de novo drug design environment [27] with encouraging results, which shows that the method described in this article is valid for more than one system.…”

Assessing Synthetic Accessibility of Chemical Compounds Using Machine Learning Methods

“…An implicit inclusion of synthesizability constraints is implemented in programs such as TOPAS 4 and SYNOPSIS. 5 The TOPAS uses only the fragments obtained from known drugs using a reaction-based fragmentation procedure similar to RECAP. 6 Instead of using the small fragments, SYNOPSIS uses the whole molecules in the available molecules library as fragments.…”