Record Details

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

DIR@IMTECH: CSIR-Institute of Microbial Technology

View Archive Info
 
 
Field Value
 
Title Gaussian field-based 3D-QSAR and molecular simulation studies to design potent pyrimidine-sulfonamide hybrids as selective BRAF(V600E) inhibitors
 
Creator Singh, Ankit Kumar
Novak, Jurica
Kumar, Adarsh
Singh, Harshwardhan
Thareja, Suresh
Pathak, Prateek
Grishina, Maria
Verma, Amita
Yadav, Jagat Pal
Khalilullah, Habibullah
Pathania, Vikas
Nandanwar, Hemraj
Jaremko, Mariusz
Emwas, Abdul-Hamid
Kumar, Pradeep
 
Subject QR Microbiology
 
Description 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.
 
Publisher Royal Society of Chemistry
 
Date 2022-10-21
 
Type Article
PeerReviewed
 
Relation https://pubs.rsc.org/en/content/articlelanding/2022/RA/D2RA05751D
http://crdd.osdd.net/open/3042/
 
Identifier 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.