Virtual screening of National Cancer Institute database for claudin ‐4 inhibitors: Synthesis, biological evaluation, and molecular dynamics studies

In the present work, structure ‐based virtual screening is performed with the National Cancer Institute (NCI) database using Glide. Molecular dynamics simulations of membrane protein were used for optimization of the top‐three lead compounds (NCI110039, NCI344682, and NCI661251) with claudin‐4 in a dynamic system. Synthesis of the NCI110039 was performed. Cytotoxicity assays proved that purpurogallin carboxylic acid has the inhibitory effect towards breast (MCF7) and lung (A549) cancer cell lines. AbstractClaudin ‐4 (CLDN4) is a vital member of tight‐junction proteins that is often overexpressed in cancer and other malignancies. The three‐dimensional structure of human CLDN4 was constructed based on homology modeling approach. A total of 265 242 molecules from the National Cancer Institute (NCI) databa se has been utilized as a dataset for this study. In the present work, structure‐based virtual screening is performed with the NCI database using Glide. By molecular docking, 10 candidate molecules with high scoring functions, which binds to the active site of CLDN4 were identified. Subsequently, molecular dynamics simulations of membrane protein were used for optimization of the top‐three lead compounds (NCI110039, NCI344682, and NCI661251) with CLDN4 in a dynamic system. The lead molecule from NCI database NCI11039 (purpurogallin carboxylic acid) was synthesized and cytotoxic properties were evaluated with A549, MCF7 cell lines. Our docking and dynamics simula...
Source: Journal of Cellular Biochemistry - Category: Biochemistry Authors: Tags: RESEARCH ARTICLE Source Type: research