TY - GEN
T1 - Fragment-Based Drug Design to Discover Novel Inhibitor of Dipeptidyl Peptidase-4 (DPP-4) as a Potential Drug for Type 2 Diabetes Therapy
AU - Ningsih, Eka Gunarti
AU - Hidayat, Muhammad Fauzi
AU - Tambunan, Usman Sumo Friend
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Diabetes mellitus is among the highest cause of death in the world. Medicinal treatment of diabetes mellitus can be achieved by inhibiting Dipeptidyl Peptidase-4 (DPP-4). This enzyme rapidly inactivates incretin, which acts as a glucoregulatory hormone in the human body. Fragment-based drug design through computational studies was conducted to discover novel DPP-4 inhibitors. About 7,470 fragments out of 343,798 natural product compounds were acquired from applying Astex Rule of Three. The molecular docking simulation was performed on the filtered fragments against the binding site of DPP-4. Fragment-based drug design was carried out by growing new structures from the potential fragments by employing DataWarrior software. The generated ligand libraries were evaluated based on the toxicity properties before underwent virtual screening, rigid, and induced-fit molecular docking simulation. Selected ligands were subjected to the pharmacological and toxicological property analysis by applying DataWarrior, Toxtree, and SWISSADME software. According to the ligand affinity, which based on the ∆G binding value and molecular interaction along with the pharmacological properties of the ligand, two best ligands, namely FGR-2 and FGR-3, were chosen as the novel inhibitor of DPP-4. Further in vitro, in vivo, and clinical trial analysis must be executed in order to validate the selected ligands therapeutic activity as drug candidates for type 2 diabetes.
AB - Diabetes mellitus is among the highest cause of death in the world. Medicinal treatment of diabetes mellitus can be achieved by inhibiting Dipeptidyl Peptidase-4 (DPP-4). This enzyme rapidly inactivates incretin, which acts as a glucoregulatory hormone in the human body. Fragment-based drug design through computational studies was conducted to discover novel DPP-4 inhibitors. About 7,470 fragments out of 343,798 natural product compounds were acquired from applying Astex Rule of Three. The molecular docking simulation was performed on the filtered fragments against the binding site of DPP-4. Fragment-based drug design was carried out by growing new structures from the potential fragments by employing DataWarrior software. The generated ligand libraries were evaluated based on the toxicity properties before underwent virtual screening, rigid, and induced-fit molecular docking simulation. Selected ligands were subjected to the pharmacological and toxicological property analysis by applying DataWarrior, Toxtree, and SWISSADME software. According to the ligand affinity, which based on the ∆G binding value and molecular interaction along with the pharmacological properties of the ligand, two best ligands, namely FGR-2 and FGR-3, were chosen as the novel inhibitor of DPP-4. Further in vitro, in vivo, and clinical trial analysis must be executed in order to validate the selected ligands therapeutic activity as drug candidates for type 2 diabetes.
KW - Dipeptidyl Peptidase-4
KW - Fragment-based drug design
KW - In silico
KW - Natural compounds
KW - Type 2 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85065820461&partnerID=8YFLogxK
U2 - 10.1007/978-3-030-17938-0_2
DO - 10.1007/978-3-030-17938-0_2
M3 - Conference contribution
AN - SCOPUS:85065820461
SN - 9783030179373
T3 - Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)
SP - 14
EP - 24
BT - Bioinformatics and Biomedical Engineering - 7th International Work-Conference, IWBBIO 2019, Proceedings
A2 - Ortuño, Francisco
A2 - Valenzuela, Olga
A2 - Rojas, Ignacio
A2 - Rojas, Fernando
A2 - Ortuño, Francisco
PB - Springer Verlag
T2 - 7th International Work-Conference on Bioinformatics and Biomedical Engineering, IWBBIO 2019
Y2 - 8 May 2019 through 10 May 2019
ER -