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.

Hepatitis B immunoglobulin prophylaxis after liver transplantation: experience in a tertiary transplant centre.

BACKGROUND: Prophylaxis with hepatitis B immunoglobulin (HBIG) and nucleoside analogs can prevent hepatitis B virus (HBV) recurrence after liver transplant (LT). AIM: To determine the efficacy and cost of maintaining immunoprophylaxis with HBIG and hyperimmune plasma (HIP) for 6 months after LT. MATERIAL & METHODS: The study included 22 HBV related LT recipients who were on entecavir and either HBIG or HIP for 6 months. Post transplant HBIG or HIP dose and cost incurred towards prophylaxis were noted. The cost of 200 IU of HBIG at the time of study was Rs 8250/- (US Dollars 135) and that of 2000 IU of HIP was Rs 8000/- (USD 130.7). The loading and maintenance costs at end of 6 months were compared between the two groups. Response to HBIG and HIP was assessed by checking for HBsAg reactivity, anti HBs titer response and HBV DNA viral load. STATISTICAL ANALYSIS: Median and range, Kruskal Wallis (KW) sign rank Sum Test and Correlation Coefficient (r2) was used for analysis. RESULTS: Thirteen recipients received HBIG and 9 recipients HIP. The anti HBs response to HIP was significantly high compared to HBIG (KW Sign rank Sum test P < 0.05); titers remained high until the study period. Between 8 and 30 days, the titer achieved by both HBIG and HIP was similar (KW Sign rank Sum test not significant). Despite low anti HBs titer of <100 IU/L, none of the recipients on HBIG had HBsAg reactivity while 3 on HIP had transient HBsAg positivity. The total cost with HBIG was 13.9 times the cost of HIP. CONCLUSION: HIP immunoprophylaxis in combination with entecavir achieves a high anti HBs titer at a significant low cost during anhepatic and loading phase. HBV reactivation rates with HBIG and HIP is low despite low anti HBs titer.