Ruđer Bošković Institute Research Data Repository
| Title (english) | Oxo-tetrahydro-pyrimidin-benzenesulfonamide Hybrids as Potential BRAFV600E Inhibitors: Experimental, Computational and Biological Evaluations |
| Author | Jurica Novak Ruđer Bošković Institute |
| Collaborator | Prateek Pathak (Researcher) School of Pharmacy, GITAM (Deemed to be University), Hyderabad Campus, India |
| Scientific / art field, discipline and subdiscipline | NATURAL SCIENCES Chemistry Physical Chemistry |
| Abstract (english) | The MAPK signaling pathway, comprising RAS, RAF, MEK, and ERK, plays a critical role in cellular proliferation and survival. Mutations in this pathway, particularly in BRAF, are implicated in various cancers, including melanoma (70–90%), thyroid cancer (30–50%), and others. Pyrimidine-sulfonamide derivatives have previously shown potent anticancer activity against mutant BRAF proteins. In this study, we synthesized urea-based pyrimidine cyclized sulfonamide derivatives and evaluated their... More |
| Methods (english) | The geometries of the top two compounds exhibiting the highest inhibition of BRAF protein in the BRAFV600E kinase assay (S1 and S4), along with the reference drug sorafenib, were optimized using second-order Møller–Plesset perturbation theory (MP2) with the 6-31G* basis set. Atomic charges were derived from the electrostatic potential, calculated at selected points using the Merz–Singh–Kollman scheme and the HF/6-31G* method. Parameterization for molecular dynamics (MD) simulations employed the AMBER 22 Antechamber module, utilizing the General AMBER Force Field (GAFF2) for ligands and the AMBER ff19SB force field for the protein. Protonation states of side chains were adjusted to physiological pH (7.4) using the PDB2PQR web server. Initial geometries of the ligand–protein complexes for MD simulations were obtained from molecular docking experiments. These parameterized complexes were solvated in a truncated octahedral box filled with pre-equilibrated OPC water molecules, ensuring a minimum distance of 12 Å between any solute atom and the box boundary. The solvated system was neutralized by adding six chloride ions, followed by additional sodium and chloride ions to achieve a final salt concentration of 0.15 M, as recommended by Machado and Pantano. MD simulations were conducted under physiological conditions (310 K, 1 atm) following a validated minimization–heating–equilibration–production protocol. Energy minimization was performed in two stages: the first involved 10,000 cycles (4,000 steepest descent followed by 6,000 conjugate gradient) with harmonic restraints (k = 10.0 kcal·mol-1·Å-2) on all non-solvent atoms, while the second stage was performed without any restraints. Systems were then gradually heated from 0 K to 300 K over 500 ps, followed by 500 ps of equilibration at constant temperature and pressure. A 300 ns production run was performed using a 2 fs time step, with temperature regulation via a Langevin thermostat (collision frequency: 1 ps-1). Hydrogen atoms were constrained using the SHAKE algorithm, and long-range electrostatics were treated with the particle mesh Ewald method, applying an 11 Å cutoff for non-bonded interactions. Periodic boundary conditions were maintained throughout. All simulations were executed in triplicate on the Supek supercomputer at the University of Zagreb’s University Computing Center (SRCE), using the AMBER 22 software suite. |
| Keywords (english) | |
| Language | english |
| URN:NBN | urn:nbn:hr:241:411570 |
| Publication | 2025-01-14 |
| Geolocation | Croatia |
| Publisher | Institut Ruđer Bošković Ruđer Bošković Institute |
| Access conditions | Open access |
| Terms of use |  |
| Created on | 2025-01-08 12:26:37 |
