Towards design of drugs and delivery systems with the Martini coarse-grained model

Abstract

Coarse-grained (CG) modelling with the Martini force field has come of age. By combining a variety of bead types and sizes with a new mapping approach, the newest version of the model is able to accurately simulate large biomolecular complexes at millisecond timescales. In this perspective, we discuss possible applications of the Martini 3 model in drug discovery and development pipelines and highlight areas for future development. Owing to its high simulation efficiency and extended chemical space, Martini 3 has great potential in the area of drug design and delivery. However, several aspects of the model should be improved before Martini 3 CG simulations can be routinely employed in academic and industrial settings. These include the development of automatic parameterisation protocols for a variety of molecule types, the improvement of backmapping procedures, the description of protein flexibility and the development of methodologies enabling efficient sampling. We illustrate our view with examples on key areas where Martini could give important contributions such as drugs targeting membrane proteins, cryptic pockets and protein-protein interactions and the development of soft drug delivery systems.

Keywords: Martini; PROTACS; coarse-grained models; cryptic pockets; drug delivery; drug design; lipid nanoparticles; molecular dynamics; protein-protein interactions; soft delivery systems; transmembrane proteins.

Graphical abstract

Fig. 1.

Schematic representation of a GPCR (PDB IDs 5XEZ & 6LMK) in inactive (left) and active (right) conformations with an allosteric and peptide ligand bound, respectively. Large conformational changes occur upon binding of the peptide ligand and G_s-protein binding intracellularly, which represent possible dynamics that could be observed with Martin combined with Gō-models. The allosteric pocket in the transmembrane domain exemplifies the possibility to use Martini models for identifying transmembrane pockets, allosteric or cryptic, in various complex membrane compositions. Once a ligand is bound, backmapping is a possibility to obtain higher resolution information for further ligand optimisation or design. All figures were rendered using VMD (Humphrey et al., 1996).

Fig. 2.

Important steps in PROTAC design for drug discovery campaigns. (a) Protein–protein docking either at the atomistic (ribbons) or coarse-grained level (red and cyan spheres). The E3 ligase is represented in red and the target protein in blue. (b) Coarse-graining of a small -molecule using the Martini 3 force field. (c) Dynamical motions of the ligase and the target (blue and red arrows, respectively) are important to query ternary complex stability in the presence of the PROTAC (represented as van der Waals spheres). All figures were rendered using VMD (Humphrey et al., 1996). The ternary complex structure is from Nowak et al. (2018) with the PDB ID code 6BN7.

Fig. 3.

CG modelling enables predictions of organisation, size and stability of SNs containing various building blocks and cargo. Moreover, it can be used to study the interaction between various SN formulations and biological barriers, such as plasma and endosomal membranes. All figures were rendered using VMD (Humphrey et al., 1996).