Optimization of antisense drug design against conservative local motif in simulant secondary structures of HER-2 mRNA and QSAR analysis.
نویسندگان
چکیده
AIM To study the role of mRNA secondary structure stability in antisense drug design and obtain better antisense candidates against neu/HER-2/erbB-2 mRNA than previous report. METHODS Program RNAstructure was utilized to simulate the secondary structures of HER-2 mRNA. Then 21 antisense phosphorothioate oligodeoxynucleotides (S-ODN) targeting different parts of secondary structural motif were designed. HA4 was set as positive control. Mean 50 % inhibitory effects (IC(50)) of S-ODN on proliferations of SK-BR-3 breast cancer cells were evaluated. The expression of target mRNA was detected by RT-PCR. The multiple regression and quantitative structure-activity relationship (QSAR) analysis was preformed by SPSS software. RESULTS One optimal and two suboptimal secondary structures of target mRNA were obtained. Nine out of 11 S-ODN against completely conservative local motif (LM) (conservative among all simulant secondary structures) got lower or similar IC(50) values compared with HA4. On the other hand, 2 out of 3 S-ODN against relatively conservative LM (conservative between any two simulant secondary structures) got lower or similar IC(50) values compared with HA4. Only 2 out of 5 S-ODN targeting variable LM (variable among different predicted secondary structures) had acceptable activities. Average IC(50) of S-ODN against completely conservative LM was significantly lower than that of S-ODN against diverse LM. QSAR analysis suggested that stability, base number of bulge loops, and target free energies Delta GoT were statistically significant. In the multiple regression, R was 0.967, P=0.005. CONCLUSION Antisense drug design against conservative LM was helpful for improving the positive rate. Several S-ODN candidates better than positive control were screened.
منابع مشابه
ISOGEOMETRIC TOPOLOGY OPTIMIZATION OF STRUCTURES CONSIDERING WEIGHT MINIMIZATION AND LOCAL STRESS CONSTRAINTS
The Isogeometric Analysis (IA) is utilized for structural topology optimization considering minimization of weight and local stress constraints. For this purpose, material density of the structure is assumed as a continuous function throughout the design domain and approximated using the Non-Uniform Rational B-Spline (NURBS) basis functions. Control points of the density surface are...
متن کاملComparative QSAR Analysis of 3,5-bis (Arylidene)-4-Piperidone Derivatives: the Development of Predictive Cytotoxicity Models
1-[4-(2-Alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones are a novel class of potent cytotoxic agents. These compounds demonstrate low micromolar to submicromolar IC50 values against human Molt 4/C8 and CEM T-lymphocytes and murine leukemia L1210 cells. In this study, a comparative QSAR investigation was performed on a series of 3,5-bis(arylidene)-4-piperidones using different ...
متن کاملComparative QSAR Analysis of 3,5-bis (Arylidene)-4-Piperidone Derivatives: the Development of Predictive Cytotoxicity Models
1-[4-(2-Alkylaminoethoxy)phenylcarbonyl]-3,5-bis(arylidene)-4-piperidones are a novel class of potent cytotoxic agents. These compounds demonstrate low micromolar to submicromolar IC50 values against human Molt 4/C8 and CEM T-lymphocytes and murine leukemia L1210 cells. In this study, a comparative QSAR investigation was performed on a series of 3,5-bis(arylidene)-4-piperidones using different ...
متن کاملSTRUCTURAL SYSTEM RELIABILITY-BASED OPTIMIZATION OF TRUSS STRUCTURES USING GENETIC ALGORITHM
Structural reliability theory allows structural engineers to take the random nature of structural parameters into account in the analysis and design of structures. The aim of this research is to develop a logical framework for system reliability analysis of truss structures and simultaneous size and geometry optimization of truss structures subjected to structural system reliability constraint....
متن کاملStructure Optimization of Neuraminidase Inhibitors as Potential Anti-influenza (H1N1Inhibitors) Agents Using QSAR and Molecular Docking Studies
The urgent need of neuraminidase inhibitors (NI) has provided an impetus for understanding the structure requisite at molecular level. Our search for selective inhibitors of neuraminidase has led to the identification of pharmacophoric requirements at various positions around acyl thiourea pharmacophore. The main objective of present study is to develop selective NI, with least toxicity and dru...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Acta pharmacologica Sinica
دوره 24 9 شماره
صفحات -
تاریخ انتشار 2003