An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge

Abstract

Molecular dynamics (MD) has become increasingly popular due to the development of hardware and software solutions and the improvement in algorithms, which allowed researchers to scale up calculations in order to speed them up. MD simulations are usually used to address protein folding issues or protein-ligand complex stability through energy profile analysis over time. In recent years, the development of new tools able to deeply explore a potential energy surface (PES) has allowed researchers to focus on the dynamic nature of the binding recognition process and binding-induced protein conformational changes. Moreover, modern approaches have been demonstrated to be effective and reliable in calculating some kinetic and thermodynamic parameters behind the host-guest recognition process. Starting from all of these considerations, several efforts have been made in order to integrate MD within the virtual screening process in drug discovery. Knowledge retrieved from MD can, in fact, be exploited as a starting point to build pharmacophores or docking constraints in the early stage of the screening campaign as well as to define key features, in order to unravel hidden binding modes and help the optimisation of the molecular structure of a lead compound. Based on these outcomes, researchers are nowadays using MD as an invaluable tool to discover and target previously considered undruggable binding sites, including protein-protein interactions and allosteric sites on a protein surface. As a matter of fact, the use of MD has been recognised as vital to the discovery of selective protein-protein interaction modulators. The use of a dynamic overview on how the host-guest recognition occurs and of the relative conformational modifications induced allows researchers to optimise small molecules and small peptides capable of tightly interacting within the cleft between two proteins. In this review, we aim to present the most recent applications of MD as an integrated tool to be used in the rational design of small molecules or small peptides able to modulate undruggable targets, such as allosteric sites and protein-protein interactions.

Homology Modeling-Based in Silico Affinity Maturation Improves the Affinity of a Nanobody

“…On the Nb02 structure, we ran 50 ns MD (Molecular Dynamics) simulation to eliminate unreasonable clashes and minimize energy, and analyze the whole production run and choose the lowest internal potential energy for subsequent analysis [34]. Compared to the modeled structure, significant conformational rearrangements were observed in their CDRs (Complementarity determining regions), especially with the CDR3 (as in Figure 2a).…”

In Silico Insights towards the Identification of NLRP3 Druggable Hot Spots

“…Our investigation was further extended by performing 500 ns MD using Desmond [23], with the aim of evaluating the complex stability [24]. MD was launched starting from the best retrieved XP docking pose.…”

Targeting SARS‐CoV‐2 RBD Interface: a Supervised Computational Data‐Driven Approach to Identify Potential Modulators

“…[62] These residues are mainly hydrophobic and usually widely dislocated along the whole protein surfaces, and thus sequentially not connected among them within the same protein, creating a discontinuous epitope. [63][64][65] Notably, from the currently available PDB structures of ACE2-S protein interaction (PDB IDs: 6M17 and 6M0J), the complex shows a one to one interaction pattern, where the contacts between the two proteins are mediated mainly by hydrogen bonds, some salt bridges and few Van der Waals forces. Due to the width of this protein-protein interface, it was possible to identify three regions of interaction, such as N-terminal, central and Cterminal regions ( Figure 2).…”