Abstract: In order to reduce the high failure rate of drug development caused by the poor drug-like properties of candidate compounds, it is helpful to improving the limitation of the descriptors in CoMFA table. By calculating the descriptors of 70 novobiocin compounds, 6122 descriptors of per compound were obtained, while only 4 critical descriptors after screening were remained. Then by adding the screened descriptors into standard CoMFA models, the best modified model was obtained by adding descriptor POS_05_-O-and PSA simultaneously. The modified model exhibit satisfying results with higher Q², R_ncv², R_pre² than that of the standard CoMFA. Moreover, the contour maps suggest the improvement for compounds, and also verifies the reliability of the model. By analyzing the distribution of the descriptor POS_05_-O-and PSA in 70 compounds, the results show that there are 20 compounds containing the descriptor POS_05_-O-and with PSA from 90 to 110, which is 90% of the active compounds. This indicates that the two descriptors are indeed significant for improving compounds activities and bioavailability.