Kinase selectivity remains a challenge to many drug discovery projects. To design molecules with selectivity built in requires chemists to either know or be able to visualize the different protein active sites and how the proposed molecule will fit within the target and be selective against other kinase targets. Seemingly this would suggest that designing in 3D should be a prerequisite for creating selective compounds. However, many molecule designers prefer to think and work in 2D and subsequently apply 3D techniques to their design. To solve this conundrum, as part of our new web-based application dedicated to molecular design we developed Grow3D, an algorithm dedicated to the real time conversion of 2D sketches into sensible 3D poses. While growing in the binding pocket of the target, the ligand should pick up favourable contacts, escape steric clashes, mimic the contacts established by known references (if any), all of which with as little user intervention as possible. Achieving these goals entails significant challenges, as a 3D conformation has far more degrees of freedom than a 2D graph. A tiny change on a 2D canvas, such as switching a bond from wedged to dashed, cyclizing a linear structure or aromatizing an alicyclic ring may trigger a major structural rearrangement and/or change in electrostatic properties. Molecules have symmetries, and it should be as obvious to the algorithm as it is to the chemist that a certain meta substituent should lie on one specific side of the phenyl ring, as it wouldn't fit on the other. Critically for kinase selectivity, the application should support multiple 3D windows, enabling designers to view their molecules in the desired target and assess their selectivity anti-target simultaneously. In this communication, we will discuss advantages and drawbacks of the Grow3D approach with reference to a worked example of kinase inhibitor design.

Is using a 2D drawing application to design for kinase selectivity an oxymoron?

2019 Fall National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.