3D‐QSAR, Molecular Docking and Molecular Dynamics Analysis of 1,2,3,4‐Tetrahydroquinoxalines as BRD4/BD2 Inhibitors

Abstract

BRD4 plays an indispensable role in cell cycle regulation, affecting processes such as cell proliferation, apoptosis and transcription. In this article, a three-dimensional quantitative conformational relationship (3D-QSAR) was used to investigate the molecular simulations related to 45 tetrahydrooxazole BRD4/BD2 selective inhibitors. 3D-QSAR models were developed based on two different analytical methods, COMFA and COMSIA. All CoMSIA field combinations were compared together and the best CoMSIA model was selected based on external validation and model prediction results. Both CoMSIA (S + E + H + D (q 2 = 0.808, r 2 = 0.99)) and CoMFA models (q 2 = 0.779;,r 2 = 0.962) predicted the internal and external well.Twenty small molecules with higher inhibitory activity than the template compound were designed by 3D-QSAR model prediction and quantum chemistry analysis, screened by molecular docking and ADMET methods, and five novel compounds were found to have better predicted activity and binding affinity. Molecular dynamics simulations showed that PRO70, PRO371, TYR428, ASN429 and VAL435 are important residues that can interact with the ligands. Moreover, further structural optimization of the more active candidate compounds will provide an essential theoretical basis of the synthesis and design of novel BRD4/BD2 inhibitors.

Synthesis of N‐(2‐(tert‐Butylamino)‐2‐oxoethyl)‐2,2‐dichloro‐N‐aryl(alkyl)acetamides as Anticancer Agents: Molecular Modeling and Biological Evaluations

“…It has been observed that the A 5 complex has a lower RMSD than other complexes, representing its more excellent stability. The RMSF of the protein reveals the stability of protein per residue throughout the simulation [23] . RMSF analyses of PDK2 backbone residues were calculated to examine the fluctuation and flexibility of amino acid residues pending equilibrium simulation.…”

“…of protein per residue throughout the simulation. [23] RMSF analyses of PDK2 backbone residues were calculated to examine the fluctuation and flexibility of amino acid residues pending equilibrium simulation. Based on the obtained results, RMSF value of more than 0.43 nm was not observed for any amino acid residues (Figure 4B).…”

Computational Studies for Development of Triazole‐Pyrimidines as Inhibitor of α‐Tubulin Receptor

“…[10] we have developed novel compounds against αtubulin receptors using several tools of computational chemistry: 3D-QSAR (CoMFA and CoMSIA), Molecular Docking, Molecular Dynamics simulation, and ADMET prediction technique. CoMFA and CoMSIA models have been successfully performed and validated by the PLS method [11] to discover more powerful compounds. [10] The binding analysis is an interesting technique that corroborates the potency of compound activity by studying the ligand-receptor interactions [12] and is confirmed by Re-docking technique on the original ligand (Guanosine-5'-Triphosphate).…”