BRCA1/TP53 tumor proteins inhibited by novel analogues of curcumin - Insight from computational modelling, dynamic simulation and experimental validation

The current study aimed to design novel curcumin analogue inhibitors with antiproliferative and antitumor activity towards BRCA1 and TP53 tumor proteins and to study their therapeutic potential by computer-aided molecular designing and experimental investigations. Four curcumin analogues were computationally designed and their drug-likeness and pharmacokinetic properties were predicted. The binding of these analogues against six protein targets belonging to BRCA1 and TP53 tumor proteins were modelled by molecular docking and their binding energies were compared with that of curcumin and the standard drug cyclophosphamide and its validated target. The stabilities of selected docked complexes were confirmed by molecular dynamic simulation (MDS) and MMGBSA calculations. The best-docked analogue was chemically synthesized, characterized, and used for in vitro cytotoxic screening using DLA, EAC, and C127I cell lines. In vivo antitumor studies were carried out in Swiss Albino Mice. The study revealed that the designed analogues satisfied drug-likeness and pharmacokinetic properties and demonstrated better binding affinity to the selected targets than curcumin. Among the analogues, NLH demonstrated significant interaction with the BRCA1-BRCT-c domain (TG3; binding energy-8.3 kcal/mol) when compared to the interaction of curcumin (binding energy-6.19 kcal) and cyclophosphamide (binding energy-3.8 kcal/mol) and its usual substrate (TG7). The MDS and MM/GBSA studies revealed that the binding free energy of the NLH-TG3 complex (-61.24 kcal/mol) was better when compared to that of the cyclophosphamide-TG7 complex (-21.67 kcal/mol). In vitro, cytotoxic studies showed that NLH demonstrated significant antiproliferative activities against tumor cell lines. The in vivo study depicted NLH possesses the potential for tumor inhibition. Thus, the newly synthesized curcumin analogue is probably used to develop novel therapeutic agents against breast cancer.