The chemical structure of a drug determines its physicochemical properties, further determines its ADME/Tox properties, and ultimately affects its pharmacological activity. Medicinal chemists can regulate the pharmacological activity of drug molecules by modifying their structure. Ring systems and functional groups are important components of a drug. The proportion of non-hydrocarbon atoms among non-hydrogen atoms reflects the heavy atoms proportion of a drug. The three factors have considerable potential for the assessment of the drug-like properties of organic molecules. However, to the best of our knowledge, there have been no studies to systematically analyze the simultaneous effects of the number of aromatic and non-aromatic rings, the number of some special functional groups and the proportion of heavy atoms on the drug-like properties of an organic molecule. To this end, the numbers of aromatic and non-aromatic rings, the numbers of some special functional groups and the heavy atoms proportion of 6891 global approved small drugs have been comprehensively analyzed. We first uncovered three important structure-related criteria closely related to drug-likeness, namely: (1) the best numbers of aromatic and non-aromatic rings are 2 and 1, respectively; (2) the best functional groups of candidate drugs are usually -OH, -COOR and -COOH in turn, but not -CONHOH, -SH, -CHO and -SO₃H. In addition, the -F functional group is beneficial to CNS drugs, and -NH₂ functional group is beneficial to anti-infective drugs and anti-cancer drugs; (3) the best R value intervals of candidate drugs are in the range of 0.05–0.50 (preferably 0.10–0.35), and R value of the candidate CNS drugs should be as small as possible in this interval. We envision that the three chemical structure-related criteria may be applicable in a prospective manner for the identification of novel candidate drugs and will provide a theoretical foundation for designing new chemical entities with good drug-like properties.

Conjunctival melanoma (CM) is a rare and fatal malignant eye tumor. In this study, we deciphered a novel anti-CM mechanism of a natural tetracyclic compound named as cucurbitacin B (CuB). We found that CuB remarkably inhibited the proliferation of CM cells including CM-AS16, CRMM1, CRMM2 and CM2005.1, without toxicity to normal cells. CuB can also induce CM cells G2/M cell cycle arrest. RNA-seq screening identified KIF20A, a key downstream effector of FOXM1 pathway, was abolished by CuB treatment. Further target identification by activity-based protein profiling chemoproteomic approach revealed that GRP78 is a potential target of CuB. Several lines of evidence demonstrated that CuB interacted with GRP78 and bound with a K_d value of 0.11 μmol/L. Furthermore, ATPase activity evaluation showed that CuB suppressed GRP78 both in human recombinant GRP78 protein and cellular lysates. Knockdown of the GRP78 gene significantly induced the downregulation of FOXM1 and related pathway proteins including KIF20A, underlying an interesting therapeutic perspective. Finally, CuB significantly inhibited tumor progression in NCG mice without causing obvious side effects in vivo. Taken together, our current work proved that GRP78–FOXM1–KIF20A as a promising pathway for CM therapy, and the traditional medicine CuB as a candidate drug to hinder this pathway.