A quantitative structure - toxicity relationship of drugs on rat

a quantitative structure toxicity relationship (qstr) is proposed to correlate the toxicity of drugs on rat after intravenous administration. the computational descriptors of 319 drug molecules are calculated using hyperchem software and regressed against ld50 of drugs collected from the literature. correlation coefficient (r), f value and average percentage deviation (apd) between calculated and experimental ld50 are used to evaluate the accuracy of the proposed qstr model. the best qstr model is: ld50=-639.254+3.773saa-4.786vol-21.050he-50.753log p-51.440ref+121.219pol+12.932mass+0.011te-95.494homo n=319, r=0,748, f=43 where, saa is surface area (approximate), vol molar volume, he hydration energy, log p is the logarithm of partition coefficient, ref molar refractivity, pol polarizability, mass molecular weight, te total energy and homo energy of the highest occupied molecular orbital. the apd of a number of drugs are very high and this resulted in high apd for the data set. these drugs include busulfan, calcitriol, epinephrine, triaziquone etc. and could be considered as outliers. after excluding these data points, the model is: ld50=-740.217+4.050saa-5.138vol-21.909he-50.713log p-49.662ref+120.843pol+12.742mass+0.010te-106.513homo n=309, r=0,751, f=43 small changes in the model constants showed that the model is robust and could be considered as a predictive model. because of various toxic mechanisms, high discrepancy in reported ld50 of some drugs from different references, high apd value could be justified. as an example, ld50s of dixyrazine are 37.5 and 3.75 in different references. after excluding the outliers, apd reduces to 977%. the apd could be considered as acceptable over range if the experimental discrepancies between reported ld50 from different laboratories are kept in mind.