GRAIL: GRids of phArmacophore Interaction fieLds

Abstract

In the absence of experimentally derived, three-dimensional structures of receptors in complex with active ligands, it is of high value to be able to gain knowledge about energetically favorable interaction sites solely from the structure of the receptor binding site. For de novo ligand design as well as for lead optimization, this information retrieved from the protein is inevitable. The herein presented method called GRAIL combines the advantages of traditional grid-based approaches for the identification of interaction sites and the power of the pharmacophore concept. A reduced pharmacophoric abstraction of the target system enables the computation of all relevant interaction grid maps in short amounts of time. This allows one to extend the utility of a grid-based method for the analysis of large amounts of coordinate sets obtained by long-time MD simulations. In this way it is possible to assess conformation dependent characteristics of key interactions over time. Furthermore, conformational changes of the protein can be taken into account easily and information thus obtained well-guides a rational ligand design process. A study employing MD trajectories of the oncology target heat shock protein 90 showcases how well our novel approach GRAIL performs for a set of different inhibitors bound to their target protein and how molecular features of the inhibitors are subject to optimization.

Next generation 3D pharmacophore modeling

“…The combination of 3D pharmacophore models with MDs is therefore a consequent evolution with great potential. Different approaches to integrating MDs into 3D pharmacophore modeling have been reported and described in this review . However, only the dynophore method represents a fully automated approach, which tackles two drawbacks of classical 3D pharmacophores at a time .…”

“…GRAIL ( 2018 ). The GRids of phArmacophore Interaction fieLds (GRAIL) approach depicts MIFs on the pharmacophore level in MD simulations . Beside pharmacophoric interaction fields, this approach generates information on atom densities for protein, water, and ligand if present.…”

A structure–kinetic relationship study using matched molecular pair analysis

“…In our work, we have provided examples for slowing down association rates by introducing polar moieties to a small molecule, which will have to be desolvated while entering the binding pocket. 24,50 Furthermore, we have provided structural insight on how the residence time can remain unaltered, even though individual contributions of K D and k on change significantly. The trend we aim to illustrate is that the addition of polar moieties to small molecules tends to affect on-rates if their desolvation is part of the binding process.…”

Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-TB Inhibitor Design: A Case Study With Mtb-DapB

“…These chemotypes can form specific stable interactions with multiple binding sites of the target offering better specificity and scope for introducing chemical diversity (Duckworth et al, 2011;San Jose et al, 2013). In recent years, target specific interactions in the form of pharmacophore models for virtual screening gained immense popularity (Schuetz et al, 2018;Schaller et al, 2020).…”