Understanding and exploiting druggable conformations

Proteins adopt a variety of conformations to exert their biological function. This conformational flexibility implies the variation of the size and availability of binding sites, which paves the way for designing drugs with distinct affinity and selectivity.

Drug-target interactions often entail conformational rearrangements in one or both of the binding partners. Several mechanisms explain this: compounds capable of inducing conformational changes in the target, compounds that bind exclusively to specific conformations or molecules that form covalent complexes.

Assessing the parameters that define the steps of the binding mechanism is pivotal for the successful optimization of promising compounds.

Applications

  • Obtain structural information in the absence of crystal structures.
  • Enhanced decision-making: Ideal hit-to-lead and lead optimization tool to exploit protein flexibility.
  • Improve optimization through detailed mechanistic profiling: Explore the mechanisms behind simple reversible compounds, those binding to specific conformations or eliciting conformational changes in the target, and reversible or irreversible covalent inhibitors.
  • Understand PK/PD disconnects: Kinetic profiling often bridges the gap between PK/PD prediction and observation.
  • Build better models: PK/PD models that integrate kinetics better predict target engagement, drug dose and treatment schedule.

    Technology

    COVALfinder®

    COVALfinder® is a kinetic screening platform that provides in-depth understanding of the binding mechanism of reversible, reversible covalent and irreversible drugs to iterate medicinal chemistry, understand PK/PD disconnects and build better models to define therapeutic windows.

    List of targets ready to use

    Our expertise extends beyond kinases to GPCR and other target types.

    Search our database to discover whether your target is:
    • May be possible: We have a strong track record of achievement where others fail! Contact us to find out more.
    • Clear line of sight: Establishment requires finalization / validation, which typically takes 2-4 weeks to complete.
    • Good to go: Data within 2 weeks of compound receipt.

    * Full length and partial length forms are available.

    Target name Alternative names KINETICfinder COVALfinder
    AAK1 KIAA1048, DKFZp686K16132 Clear line of sight
    ABL1 ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Good to go
    ABL1 E255K ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Clear line of sight
    ABL1 G250E ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Clear line of sight
    ABL1 H396P ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Clear line of sight
    ABL1 M351T ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Clear line of sight
    ABL1 Q252H ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Clear line of sight
    ABL1 Y253F ABL, c-ABL1, BCR-ABL, CHDSKM, JTK7, bcr/abl, c-ABL, p150, v-abl Clear line of sight
    ABL2 (ARG) ARG, ABL isoform b, ABLL Good to go
    ACK (TNK2) TNK2, ACK-1, ACK1, p21cdc42Hs Good to go
    ACVR2A ACTRII, ACTR2, ACVR2 Clear line of sight
    ACVR2B ACTRIIB, ActR-IIB, HTX4 Clear line of sight
    AKT1 AKT1, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA, Good to go
    ALK ALK, CD246, NBLST3 Good to go May be possible
    ALK C1156Y ALK, CD246, NBLST3 Clear line of sight
    ALK F1174L ALK, CD246, NBLST3 Clear line of sight
    ALK L1196M ALK, CD246, NBLST3 Clear line of sight
    ALK R1275Q ALK, CD246, NBLST3 Clear line of sight
    ALK T1151_L1152insT ALK, CD246, NBLST3 Clear line of sight
    ALK1 (ACVRL1) ALK1, ALK-1, ACVRLK1, HHT, HHT2, ORW2, SKR3, TSR-I Good to go May be possible

    How can we help?

    Our experienced project manager will work with you to identify the best way forward for your project.