creators_name: Singh, Ankit Kumar creators_name: Novak, Jurica creators_name: Kumar, Adarsh creators_name: Singh, Harshwardhan creators_name: Thareja, Suresh creators_name: Pathak, Prateek creators_name: Grishina, Maria creators_name: Verma, Amita creators_name: Yadav, Jagat Pal creators_name: Khalilullah, Habibullah creators_name: Pathania, Vikas creators_name: Nandanwar, Hemraj creators_name: Jaremko, Mariusz creators_name: Emwas, Abdul-Hamid creators_name: Kumar, Pradeep type: article datestamp: 2022-12-15 08:22:09 lastmod: 2022-12-15 08:22:09 metadata_visibility: show title: Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAF(V600E) inhibitors ispublished: pub subjects: QR note: The copyright of this article belongs to Royal Society of Chemistry abstract: The "RAS-RAF-MEK-ERK" pathway is an important signaling pathway in melanoma. BRAFV600E (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 I1/2 (αC-OUT/DFG-IN), and type I/II (αC-OUT/DFG-OUT). First- and second-generation BRAF inhibitors show resistance to BRAFV600E 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 BRAFV600E inhibitors. Analysis of 3D-QSAR models provided novel pyrimidine sulfonamide hybrid BRAFV600E inhibitors. The designed compounds share similarities with several structural moieties present in first- and second-generation BRAF inhibitors. A total library of 88 designed compounds was generated and molecular docking studies were performed with them. Four molecules (T109, T183, T160, and T126) were identified as hits and selected for detailed studies. Molecular dynamics simulations were performed at 900 ns and binding was calculated. Based on molecular docking and simulation studies, it was found that the designed compounds have better interactions with the core active site [the nucleotide (ADP or ATP) binding site, DFG motif, and the phospho-acceptor site (activation segment) of BRAFV600E protein than previous inhibitors. Similar to the FDA-approved BRAFV600E inhibitors the developed compounds have [αC-OUT/DFG-IN] conformation. Compounds T126, T160 and T183 interacted with DIF (Leu505), making them potentially useful against BRAFV600E resistance and malignancies induced by dimer BRAF mutants. The synthesis and biological evaluation of the designed molecules is in progress, which may lead to some potent BRAFV600E selective inhibitors. date: 2022-10-21 date_type: published publication: RSC ADVANCES volume: 12 number: 46 publisher: Royal Society of Chemistry pagerange: 30181-30200 refereed: TRUE official_url: https://pubs.rsc.org/en/content/articlelanding/2022/RA/D2RA05751D citation: Singh, Ankit Kumar and Novak, Jurica and Kumar, Adarsh and Singh, Harshwardhan and Thareja, Suresh and Pathak, Prateek and Grishina, Maria and Verma, Amita and Yadav, Jagat Pal and Khalilullah, Habibullah and Pathania, Vikas and Nandanwar, Hemraj and Jaremko, Mariusz and Emwas, Abdul-Hamid and Kumar, Pradeep (2022) Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAF(V600E) inhibitors. RSC ADVANCES, 12 (46). pp. 30181-30200.