Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAF^V600E inhibitors.

ABSTRACT: The "RAS-RAF-MEK-ERK" pathway is an important signaling pathway in melanoma. BRAF^V600E (70-90%) is the most common mutation in this pathway. BRAF inhibitors have four types of conformers: type I (αC-IN/DFG-IN), type II (αC-IN/DFG-OUT), type I_1/2 (αC-OUT/DFG-IN), and type I/II (αC-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAF^V600E and are ineffective against malignancies induced by dimer BRAF mutants causing 'paradoxical' activation. In the present study, we performed molecular modeling of pyrimidine-sulfonamide hybrids inhibitors using 3D-QSAR, molecular docking, and molecular dynamics simulations. Previous reports reveal the importance of pyrimidine and sulfonamide moieties in the development of BRAF^V600E inh

SUBMITTER: Singh AK 

PROVIDER: S-EPMC9585928 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature