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. 2025 Feb 5;10(7):6650-6662.
doi: 10.1021/acsomega.4c08049. eCollection 2025 Feb 25.

Molecular Glue-Design-Evaluator (MOLDE): An Advanced Method for In-Silico Molecular Glue Design

A S Ben Geoffrey  1 , Deepak Agrawal  1 , Nagaraj M Kulkarni  1 , Manonmani Gunasekaran  1
Affiliations

Molecular Glue-Design-Evaluator (MOLDE): An Advanced Method for In-Silico Molecular Glue Design

A S Ben Geoffrey et al. ACS Omega. .

Erratum in

Abstract

Protein function modulation using small-molecule binding is an important therapeutic strategy for many diseases. However, many proteins remain undruggable due to the lack of suitable binding pockets for small-molecule binding. Proximity-induced protein degradation using molecular glues has recently been identified as an important strategy to target undruggable proteins. Molecular glues were discovered serendipitously and as such currently lack an established approach for in-silico-driven rationale design. In this work, we aim to establish an in-silico method for designing molecular glues. To achieve this, we leverage known molecular glue-mediated ternary complexes and derive a rationale for the in-silico design of molecular glues. Establishing an in-silico rationale for molecular glue design would significantly contribute to the literature and accelerate the discovery of molecular glues for targeting previously undruggable proteins. Our work presented here and named Molecular Glue-Designer-Evaluator (MOLDE) contributes to the growing literature of in-silico approaches to drug design in-silico literature.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
In-silico-driven molecular glue design method (MOLDE: Molecular Glue Design & Evaluator).
Figure 2
Figure 2
Experimental pose reproduced in protein–protein docking.
Figure 3
Figure 3
Analysis of the pocket formation at the interface of the two proteins for PPI_Pose_2.
Figure 4
Figure 4
Pose of RC8 reproduced in DDB1-CDK12 and the resulting ternary complex.
Figure 5
Figure 5
Identification pocket suitable for molecular glue binding formed at the interface of cereblon-SALL4 through protein–protein docking.
Figure 6
Figure 6
Pose of the molecular glue in the PDB entry 7BQV system.
Figure 7
Figure 7
Identification pocket suitable for molecular glue binding formed at the interface of DDB1_Assembly-BRD4 through protein–protein docking.
Figure 8
Figure 8
Reproducing the pose of the molecular glue in the PDB entry 8G46 system.
Figure 9
Figure 9
YK3 as a representative example for molecular glues that work through covalent interactions.
Figure 10
Figure 10
RC8 as a representative example for molecular glues that work through noncovalent interaction.
Figure 11
Figure 11
RMSD stabilization of the PDB 8G46 system with and without the molecular glue.
Figure 12
Figure 12
RMSD stabilization of the PDB 7TE8 system with and without the molecular glue.
Figure 13
Figure 13
RMSD stabilization of the PDB 6TD3 system with and without the molecular glue.
Figure 14
Figure 14
RMSD stabilization of the PDB 7BQU system with and without the molecular glue.
Figure 15
Figure 15
RMSD stabilization of the PDB 7BQV system with and without the molecular glue.
Figure 16
Figure 16
Molecular glue allostery-mediated CRBN-CK1α interaction.
Figure 17
Figure 17
RMSD stabilization of DDB1-Cyclin_dependent_kinase_12 ternary complex stabilized by SAIT_MG_26121.
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