Analysis of binding conformations of drugs to human serum albumin (site I and site II) by NMR measurements and computational calculations

点击翻译按钮获取中文摘要

(1) The binding conformations of drugs to site I and site II of HAS has been investigated by CAMDAS, SUPERPOSE and TRNOE experiments. We have combined distance information obtained from CAMDAS and TRNOE to perform an extraction of a "binding conformer" for drugs binding to the HAS (site I and site II ).(2) Site I binding drugsFor BMT, one selected conformer (BMT354) was obtained. The basic binding conformer structure of BMT354 was taken as a "template" to choose binding conformers for FUCI and IM. Consequently, we could efficiently select one binding conformer for FUCI and IM.(3) Site II binding drugsFor tolmetin (TLM), only one conformer (TLM 53) among conformers generated by CAMDAS satisfied the distance restraint conditions obtained from NOESY. The structure of the TLM (conf53) was taken as a "template" to choose binding conformers for other drugs by molecular overlay. We could efficiently select one binding conformer for ETH-A, R-IB, S-IB, R-KP and S-KP.(4) Then, we constructed the complex structure of drugs (BMT354, TLM53) and HAS based on the crystal structure of HAS using Flexi Dock program implemented in SYBYL (Tripos).This method of combining MD calculation, SUPERPOSE and TRNOE measurements suggested to an extremely effective method for obtaining steric conformation for drugs bound to HAS.Binding conformer of the drugs in the binding site (site I and site II ) of HAS was used to probe the drug-HAS complementary interactions.