Theoretical research in structure characteristics of different inhibitors and differences of binding modes with CBP...

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• The CREB (cAMP responsive element binding protein) binding protein (CBP) bromodomain (BRD) recognizes acetylated lysine 382 on the human tumor suppressor protein p53.
• Mutations in the p53 gene are linked to various human cancers.
• CBP-BRD is a validated drug target for numerous disease pathways, with existing effective drugs.

Purpose of the Study:

• To investigate the binding modes of five inhibitors with the CBP-BRD using computational simulations.
• To identify a core fragment for designing novel CBP-BRD inhibitors.
• To evaluate the drug-likeness properties of newly designed molecules.

Main Methods:

• Molecular dynamics (MD) simulations were employed to analyze inhibitor-CBP-BRD interactions.
• Molecular mechanics generalized Born surface area (MM-GB/SA) calculations assessed binding affinities.
• LUDI and rational drug design strategies were used for de novo inhibitor design.
• T.E.S.T. and molinspiration tools evaluated oral bioavailability and potential drug promiscuity.

Main Results:

• Distinct binding modes of the five inhibitors with CBP-BRD were elucidated through MD simulations and MM-GB/SA analysis.
• A potent core fragment was identified as a promising scaffold for further drug development.
• Computational evaluation suggested favorable oral bioavailability and reduced promiscuity for novel designed molecules.

Conclusions:

• The study provides insights into the structure-activity relationships of CBP-BRD inhibitors.
• Identified core fragment and designed molecules offer a foundation for developing new anti-cancer therapeutics targeting CBP-BRD.
• Computational approaches are valuable for accelerating the drug discovery process for CBP-BRD inhibitors.