The efforts of lead optimization projects are directed towards analogs that have favorable ADME profiles and are devoid of safety concerns whilst retaining target activity. Recently, we have developed a novel computational platform called ACD/Structure Design Engine (SDE) to aid such projects by generating virtual analog libraries in the physicochemical space regions compatible with the desired biological characteristics. SDE is implemented on top of ACD/Percepta software platform that couples virtual analog generation to their physicochemical, ADME/Tox profiling and ranking by conformance to the particular project objectives. While enumeration of structural analogs falling within the desired physicochemical property ranges is quite straightforward in case of one varying substituent position, most real-world projects are focused on optimizing multiple substituents in different parts of the molecule. To address this issue, we present a new generation of SDE that would enable extensive enumeration of substituent property space in accordance with specific constraints defined by the user, and that would be able to account for up to four simultaneously varying substituent positions. Several optimization techniques allowed to bring complexity of this task from O(n4) to approximately O(n2). In such case, with a built-in database of more than 104 building blocks for each substitution position, this leads to exploration of up to 1016 virtual analogs in seconds, which allows to work with such virtual set of compounds interactively and greatly enhances the potential of encountering new compounds with the most favorable property profiles.

ACD/Percepta structure design engine: Virtual enumeration and screening of physchem properties for 10<sup>16</sup> compounds in real time

248th National Meeting (2014)

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ACD/Percepta structure design engine: Virtual enumeration and screening of physchem properties for 1016 compounds in real time

ACD/Percepta structure design engine: Virtual enumeration and screening of physchem properties for 10¹⁶ compounds in real time