Driving Structure-Based Drug Discovery through Cosolvent Molecular Dynamics

Abstract

Identifying binding hotspots on protein surfaces is of prime interest in structure-based drug discovery, either to assess the tractability of pursuing a protein target or to drive improved potency of lead compounds. Computational approaches to detect such regions have traditionally relied on energy minimization of probe molecules onto static protein conformations in the absence of the natural water environment. Advances in high performance computing now allow us to assess hotspots using molecular dynamics (MD) simulations. MD simulations integrate protein flexibility and the complicated role of water, thereby providing a more realistic assessment of the complex kinetics and thermodynamics at play. In this review, we describe the evolution of various cosolvent-based MD techniques and highlight a myriad of potential applications for such technologies in computational drug development.

Chemical‐Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors

“…MD simulations sample conformational space and provide snapshots of relevant protein conformations for docking, improving the accuracy of virtual screening over rigid protein docking . The method also facilitates discovery of allosteric sites …”

“…[8] The method also facilitates discovery of allosteric sites. [9] Bile acids have been reported as important cofactors promoting human and murine norovirus (NoV) infections in cell culture. The underlying mechanisms are not resolved.…”

In silico structure-based approaches to discover protein-protein interaction-targeting drugs

“…Molecular dynamics (MD) simulation, mimicking MSCS, is also used to predict hotspots [81]. The target protein structure is solvated with a mixture of explicit water and small molecule probes.…”

Computer-aided drug design: time to play with novel chemical matter

“…Proper inclusion of solvation and dynamic effects have transformed the predictive capability at every stage of the process. The inclusion of small organic molecules in the solvent that are used as probes (MD simulations with mixed cosolvents, or MDmix) was initially devised as a binding site identification and druggability prediction method [20,21], but is finding numerous applications, including prediction of pharmacophoric points, detection of cryptic pockets, or ligand scoring [22]. MD simulations, with or without cosolvents, also allow unprecedented characterization of the hydration preferences of binding sites, a fundamental property for ligand design [23].…”