Computer-aided design of temozolomide derivatives based on alkylglycerone phosphate synthase structure with isothiocyanate and their pharmacokinetic/toxicity prediction and anti-tumor activity in vitro

Despite the development of temozolomide (TMZ), a novel type of glioma therapeutic drug, malignant glioma remains to cause severe damage to human health. The present study aimed to utilize the molecular biological differences between tumor and normal cells to design TMZ derivatives with improved selectivity and targeting using computer-aided drug design (CADD). Taking alkylglycerone phosphate synthase (AGPS) as a target, a 3D structure-activity relationship model was built using CADD technology; molecular docking of isothiocyanate (ITC) and TMZ compounds was conducted; ITC-TMZ derivatives were designed; and predictions on the absorption, distribution, metabolism and excretion (ADME) processes and toxicity of the ITC-TMZ derivatives were established in order to obtain improved understanding of the structure-activity relationship of the candidate compounds. Using these techniques, it was identified that the docking scores of the structural derivatives S1-9 were higher than that of TMZ. Additionally, S3, −6, −7, −8, −9 and −10 exhibited enhanced ADME and similar toxicity to that of TMZ. The half maximal inhibitory concentrations of the CADD derivatives were also assessed in the glioma U87MG and U251 cell lines, and the activities of S1, −3, −8 and −10 were determined to be greater than that of TMZ, suggesting their potential as anti-cancer drugs with adequate AGPS targeting, ADME/toxicity and anti-tumor activity.