IN SILICO STUDY OF 8-TERSUBTITUSI-7-METHOXY-2H-CHROMEN-2-ONE} DERIVEITIVES AS TELOMERASE ENZYME INHIBITOR

• Main Author: Tahir, Masdiana
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/78829
• Institution: Institut Teknologi Bandung

Telomerase is a ribonucleoprotein which maintain the length of the telomeres. Adjustment of telomere length by telomerase is considered as a biological marker which determine the proliferation of cancer cells. 90% of hepatocellular carcinoma (HCC) cells express telomerase, and inhibition of the telomerase enzyme in HepG2 cells can decrease the Alpha fetoprotein (AFP), a tumor marker serum HCC. The telomerase activity in cancer cells is potewtial to be targeted cancer therapies. The purposes of the present study were to select combinations of descriptors which are highly correlates to the anticancer activity of 8-substituted-7methoxy-2H-chromen-2-one derivatives in the form of QSAR equation, to design new derivative compounds that have anticancer potency, to predict pharmacokinetic properties, and to predict tocixity and affinity to telomerase. QSAR studies werw performed by multilinear regression method using IBM SPSS Statistics 21 and 16 descriptors were calculated by using MOE@ 2009.10. Four of 16 descriptors significantly affect the anticancer activity of 8-substituted7-methoxy-2H-chromen-2-one derivatives. The calculation of the biological activity (log IC50) were as the dependent variable (Y) afid descriptors combination as the independent variables (X). QSAR equation was log IC50 ¯ 1,358 (+1,149) - 2,957 x AMI LUMO + E vdw + 2,367 (40,748) x glob + 0,487 (40,100) x log S with R = 0,925, re - 0,855, 5,44, q2 0,99, and n = 17. The new derivative compounds were designed based on QSAR equation of the lead compound 7-methoxy-8-{5-4-(methylthio)phenyl]-4-5dihydro-lH-pyrazol-3-yl}-2H-chromen-2-one. Fourteen of 61 derivatives revealed higher IC50 activity prediction than the lead compound. Furthermore, the prediction of absorption and distribution properties by using preADMET showed that 14 derivative compounds performed good absorption in Caco-2 cells in the intestine except the compound (33). It was predict that all compound strongly bounded to plasma protein except the compound (33) and (50). Toxicity prediction by ADMET predictor showed that 9 derivatives compounds (2), (4), (5), (7), (8), (12), (39), (40), and (41) were predicted to have lower nearly equal toxicity to the toxicity of the lead compound. The study of the interaction of compounds with the receptor by Autodock 4.2.6 showed that derivatives (2), (4), (40) and (41) have the highest affinity to interact with telomerase catalytic subunit (Telomerase Reverse Transcriptase-TERT) that was affected by hydrogen bond at LYS72, MET483, THR487, and ARG547, and the activities was strengthened by the hidrophobic property of the side chains attached to the pyrazole ring. In conclusion, compound (2), (4), (40), and (41) are the most potential candidate to be develop as anticancer with telomerase inhibition.