Quantification of the three point receptor hypothesis of Cheng and Zee-Cheng.
The placement of three heteroatoms at the corners of an acute angle triangle was found to correlate roughly with the antineoplastic activity of a wide range of compounds by Cheng & Zee-Cheng (1972, J. Pharm. Sci. 61, 485). Since then the synthetic routes to compounds having a large number of degrees of freedom, as in the 1,4-dihydroxy-5,8-bis([2-(2-hydroethyl)amino]ethyl) amino-9,10-anthracenedione (DHAQ, mitoxantrone) have been discovered. The subsequent high activity of DHAQ vs. numerous cancers has partially verified the worth of the original hypothesis. Quantitative verification of pharmacophoric hypotheses as theories necessitates the use of Popper's risky experiments. These experiences give rise to verification because, unenlightened by the theory undergoing testing, they would predict a result that would refute the theory. Computational chemistry allows such a confirmation through molecular modeling. The molecular force field, MMX, gives confirmation of the theory by showing the riskiness of the synthetic production of DHAQ for the gas phase. The MM+ forcefield in an aqueous medium computation (132 water molecules) shows that the confirmations of DHAQ does not change appreciably from the gas phase. This computation adds a considerable risk. Aquation could significantly change the favorable conformations of the very conformationally free DHAQ molecule. The fact that it does not confirm that the Zee-Cheng and Cheng hypothesis is a strong one. Additionally, a quantitative relationship arises from the new model for the N-O-O atomic placement. This new quantitative relationship further predicts quantitative risky experiments for further verification (falsification).
Fountain
K R
KR
Northeast Missouri State University, Kirksville 63501, USA.
Leland
C M
CM
D000970:Antineoplastic Agents / Q000378:metabolism*; D003198:Computer Simulation; D008958:Models, Molecular
D000970:Antineoplastic Agents