QUANTIFICATION OF THE 3-POINT RECEPTOR HYPOTHESIS OF CHENG AND ZEE-CHENG

The placement of three heteroatoms at the corners of an acute angle tr iangle was found to correlate roughly with the antineoplastic activity of a wide range of compounds by Cheng and Zee-Cheng (1972, J. Pharm. Sci. 61, 485). Since then the synthetic routes to compounds having a l arge number of degrees of freedom, as in the -hydroethyl)amino]ethyl}a mino-9,10-anthracenedione (DHAQ, mitoxantrone) have been discovered. T he subsequent, high activity of DHAQ vs. numerous cancers has partiall y verified the worth of the original hypothesis. Quantitative verifica tion of pharmacophoric hypotheses as theories necessitates the use of Popper's risky experiments. These experiences give rise to verificatio n 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 risk iness of the synthetic production of DHAQ for the gas phase. The MM(+) forcefield in an aqueous medium computation (132 water molecules) sho ws 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 conformat ionally free DHAQ molecule. The fact that it does not confirm that the Zee-Cheng and Cheng hypothesis is a strong one. Additionally, a quant itative relationship arises from the new model for the N-O-O atomic pl acement. This new quantitative relationship further predicts quantitat ive risky experiments for further verification (falsification).