Druggability Assessment of Targets Used in Kinetic Target-Guided Synthesis

Abstract

Kinetic target-guided synthesis (KTGS) is a powerful strategy in which the biological target selects its own inhibitors by assembling them from biocompatible reagents via an irreversible process. In this approach, the biological target accelerates the reaction between complementary building blocks by bringing them in close proximity and proper orientation. KTGS has found application on various targets. Herein, we performed a druggability assessment for each target family reported in KTGS, calculated the pocket properties, and used them to extract possible discriminating factors for successful KTGS studies. A trend for less enclosed pockets emerged, but overall we conclude that the KTGS approach is universal and could be used without restrictions regarding the physicochemical properties of the addressed pocket.

Mechanisms of Action for Small Molecules Revealed by Structural Biology in Drug Discovery

“…The database includes compound libraries and structures of a target. The available structure makes it possible to perform druggability analysis and understand the function of the target [51,52]. The structure of a target is also helpful for making suitable strategies in hit selection and lead optimization.…”

Overview of Recent Strategic Advances in Medicinal Chemistry

“…In KTGS approach, the bio-target accelerates the irreversible reaction (in situ click chemistry) between complementary fragments by bringing them into close proximity in proper orientation. 89 In 2017,…”

Protein‐Templated Hit Identification through an Ugi Four‐Component Reaction**

“…[1] In KTGS, the target is actively involved in ligand selection by assembling its own inhibitors via an irreversible reaction from al ibrary of complementaryb uilding blocks, whereas DCC assembles ligandsv ia reversible processes. [2][3][4] Only afew protein-templated reactions for KTGS have been reported so far. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] The azide-alkynec ycloaddition was the first reactionu sed for KTGS [5,[7][8][9] andi ss till by far the most widely used.…”