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The Future of Medicinal Chemistry, PROTAC, and Undruggable Drug Targets.

ABSTRACT: WRD5 is a promising target for anticancer drug discovery. In addition, it plays a vital role in epigenetic regulation. Since biological inactivation of WRD5 is difficult to reach via classical approach, PROTACs (Proteolysis Targeting Chimeras) are offering a new option. In a study, published in this journal, new WRD5 targeting PROTACS are introduced. These new compounds, which are also active in cells, make it possible to evaluate the value of WRD5 as a drug target.

SUBMITTER: Poso A

PROVIDER: S-EPMC8389887 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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.

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The Future of Medicinal Chemistry, PROTAC, and Undruggable Drug Targets.

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