Conformation-activity relationship of apoptosis-inducing phosphodiester oligonucleotides

Abstract

The present invention facilitates in silico evaluation of molecules for biological activity by providing a computer-based method to predict whether oligonucleotides may possess biological activity and the efficacy of the biological activity based on the three-dimensional structure and charge characteristics of the oligonucleotides. Biological activities include, but are not limited to, cellular proliferation, induction of cell cycle arrest and apoptosis.

1 . A computer-based method of predicting biological activity of an oligonucleotide sequence comprising analysis of the oligonucleotide sequence to determine if the oligonucleotide sequence contains at least one centrum.  
   
   
       2 . The method of  claim 1 , wherein the analysis comprises examining the sequence for electronegativity, electropositivity, intra-molecular hydrogen bonding and inter-atomic distances.  
   
   
       3 . A computer-based method of predicting biological activity of an oligonucleotide sequence comprising: drawing the sequence using chemical drawing software; checking the drawn sequence for errors; creating a three dimensional model of the drawn sequence; minimizing energy of the three dimensional model; calculating molecular dynamics using chemical analytical software; displaying a solvent accessible surface of the three dimensional model on a display means; identifying globular and linear domains in the three dimensional model; identifying intramolecular hydrogen bonds; identifying phosphate groups capable of forming an electronegative centrum; evaluating spatial orientation of bases in the three dimensional model for electropositive framing with respect to the phosphate groups in the electronegative centrum; measuring interatomic distances of amino/amido groups, and 3′ and 5′ hydroxyls from phosphate groups; and, predicting whether the sequence possesses the biological activity.  
   
   
       4 . The method of  claim 3 , wherein measuring interatomic distances of amino/amido groups and 3′ and 5′ hydroxyls from phosphate groups comprises: measuring a first interatomic distance X between phosphates associated with the centrum; measuring a second interatomic distance alpha between phosphates and a farthest atom in a participating base; measuring a third interatomic distance beta as the furthest inter-atomic distance beta between amido or amino groups; measuring a fourth interatomic distance Z between a front to a rear of the centrum; and, measuring a fifth interatomic distance Y as a longest distance between a phosphate backbone and the farthest atom in a participating base.  
   
   
       5 . The method of  claim 4 , wherein a centrum is present in the sequence if Y is equal to or between about 780 to 2200 pm; Z is equal to or between about 400 to 1300 pm; alpha is equal to or between about 900 and 1500 pm; beta is equal to or between about 300 to 1700 pm; and, X is between about 700 to 1360 pm.  
   
   
       6 . The method of  claim 1 , wherein the biological activity is inhibition of cellular proliferation, induction of cell cycle arrest or induction of apoptosis.  
   
   
       7 . The method of  claim 3 , wherein the biological activity is inhibition of cellular proliferation, induction of cell cycle arrest or induction of apoptosis.  
   
   
       8 . The method of  claim 1 , further comprising testing the sequence for the biological activity.  
   
   
       9 . The method of  claim 3 , further comprising testing the sequence for the biological activity.