Design of novel compounds as Potential DPP-4 inhibitors

Chaiyun Taomali

Chemistry

In searching for antidiabetic drugs. dipeptidyl pcptidase IV (DPP-4) was selected as a drug target in the design of new potent DPP-4 inhibitors in this study, Novel DPP-4 inhibitors were developed based on the information of medicinal herbs and structure based drug design. The DPP-4 template was prepared from DPP-4 crystal structure derived from human DPP-4 (PDB: 1X70) and validated (RMSD 0.56 A). The validated DPP-4 template was used as a target macromolecule. The combinatory library of 356 structures containing three main fragments (S1 and S2) linked with imine and amide functions was prepared. The S1 fragments are cysteine, L(-)-tryptophan and chromone while the S2 fragments are the varied side chains. Molecular docking of the structures in the library against DPP-4 template was conducted to identify the hit structures of increased binding capacity and consequently leading to potent inhibitory action. AutoDock 4.1 program was used in the docking study to identify the hit structures of good binding. The selected twenty top ranking compounds or hit compounds were identified which were 6 chromone iminc. 10 cysteine amides and 4 L(-)-tryptophan amides. The best binding free energies of compounds in each series were-11.95 kcal/mol in series C, -11.59 kcal/mol in series B and -9.0l kcaI/mol in series A. The identified hit compounds were synthesized and evaluated for the DPP-4 inhibitory action in vitro. Among sulfur containing compound, compounds 24 and 26 in the series B were most active with IC50 of 100.0 uM and the activity of all compounds in series A and series C were weak. cysteine amides 24, 26 was the most potent in this study with IC50 of 95.19 uM and 96.80 pM respectively. The uniformity of interaction across the structure and percent membership in the highest cluster from docking study appeared to have significant contribution on the activity. The binding mode of cysteine amides 24, 26 showed two hydrogen bond interactions. with Glu205 and Glu206. 'l'he designed structure 24, 26 accommodates the hydrophobic cysteine nucleus to occupy in the S-1 pocket of the enzyme and interacts with the amino acid residue in this pocket (Glu205 and Glu206) resulting in the highest potency. However, compounds 24, 26 was found to be less potent than sitagliptin. Compounds 24 and 26 are the leads for further design and modification.

Keywords: DPP-4 Inhibitors , Novel Antidiabctic Agents, Type 2 Antidiabetic

มหาวิทยาลัยราชภัฏบ้านสมเด็จเจ้าพระยา สำนักวิทยบริการและเทคโนโลยีสารสนเทศ

Atchara Keawnoi

Phansuang Udomputttimekul

Supot Jankun

2014

2021-10-18

2021-10-18

thesis

application/pdf

TH 540 C434D 2014

eng

มหาวิทยาลัยราชภัฏบ้านสมเด็จเจ้าพระยา

วิทยาศาสตรมหาบัณฑิต

ปริญญาโท

เคมี

มหาวิทยาลัยราชภัฏบ้านสมเด็จเจ้าพระยา