GRP78-targeted in-silico virtual screening of novel anticancer agents

Area of Science:

• Oncology
• Medicinal Chemistry
• Computational Biology

Background:

• Glucose-regulated protein 78 (GRP78) is overexpressed in various cancers, making it a significant target for anticancer drug development.
• Targeting GRP78 offers a promising strategy for novel therapeutic interventions against diverse malignancies.

Purpose of the Study:

• To design and identify novel GRP78 inhibitors using in-silico approaches.
• To evaluate the in vitro anticancer activity of designed compounds against selected cancer cell lines.

Main Methods:

• In-silico molecular docking simulations were performed to model interactions between GRP78 and known ligands.
• A structure-based pharmacophore hypothesis was generated and used to screen chemical databases (Asinex and Chemdiv).
• In vitro antiproliferative assays were conducted on selected cancer and normal cell lines.

Main Results:

• The GRP78-13 complex showed favorable activity and energy descriptors, leading to the development of a structure-based pharmacophore.
• Virtual screening identified 23 potential hit compounds.
• VH1019 and VH1011 exhibited significant concentration-dependent antiproliferative effects on glioma, breast, and prostate cancer cell lines.
• VH1019, an acetohydrazide derivative, demonstrated selective growth inhibition of cancer cells over normal cells with an IC50 of 12.7 μM in MCF-7 cells.

Conclusions:

• The study successfully identified novel GRP78 inhibitors with potential anticancer activity.
• VH1019 represents a promising new chemotype for the development of GRP78-targeted anticancer therapeutics.
• In-silico drug design coupled with in vitro validation is an effective strategy for identifying novel anticancer agents.