Identification of allosteric sites and allosteric inhibitors in the glucose-dependent insulinotropic polypeptide receptor via molecular simulations.
TL;DR
This study provides potential lead compounds for the design of small-molecule allosteric drugs targeting class B1 GPCRs and performs conformational sampling and combined dynamic pocket detection algorithms, MDpocket and FTMove, to identify six characteristic cryptic pockets within the dynamic trajectories.
Abstract
This study integrates long-timescale all-atom molecular dynamics (MD) simulations with multidimensional drug discovery strategies to identify potential allosteric sites of the GIPR and screen for allosteric modulators. Based on the constructed GIPR-GIP complex, we performed conformational sampling and combined dynamic pocket detection algorithms, MDpocket and FTMove, to identify six characteristic cryptic pockets within the dynamic trajectories. Subsequently, using representative conformations as templates, a structure-based virtual screening of 1.6 million compounds from the ChemDiv database was conducted, yielding 30 candidate compounds. Surface plasmon resonance (SPR) experiments showed binding responses. The cAMP accumulation assay demonstrated that compound C30 could dose-dependently antagonize GIP-induced receptor activation, displaying negative allosteric modulator (NAM) activity. MD simulations revealed that C30 primarily restricts the outward movement of the transmembrane helix TM6. This study provides potential lead compounds for the design of small-molecule allosteric drugs targeting class B1 GPCRs.