TY  - JOUR
N1  - The copyright of this article belongs to Royal Society of Chemistry
ID  - open3042
UR  - https://pubs.rsc.org/en/content/articlelanding/2022/RA/D2RA05751D
IS  - 46
A1  - Singh, Ankit Kumar
A1  - Novak, Jurica
A1  - Kumar, Adarsh
A1  - Singh, Harshwardhan
A1  - Thareja, Suresh
A1  - Pathak, Prateek
A1  - Grishina, Maria
A1  - Verma, Amita
A1  - Yadav, Jagat Pal
A1  - Khalilullah, Habibullah
A1  - Pathania, Vikas
A1  - Nandanwar, Hemraj
A1  - Jaremko, Mariusz
A1  - Emwas, Abdul-Hamid
A1  - Kumar, Pradeep
Y1  - 2022/10/21/
N2  - 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 (?C-IN/DFG-IN), type II (?C-IN/DFG-OUT), type I1/2 (?C-OUT/DFG-IN), and type I/II (?C-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 [?C-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.


PB  - Royal Society of Chemistry
JF  - RSC ADVANCES
VL  - 12
TI  - Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAF(V600E) inhibitors
SP  - 30181
EP  - 30200
ER  -