Journal of Medicinal Chemistry and Toxicology Journal of Medicinal Chemistry and Toxicology Journal of Medicinal Chemistry and Toxicology Journal of Medicinal Chemistry and Toxicology 2575-808XOmmega Online PublishersNew Jersey, USA171210.15436/2575-808X.18.1712Research ArticleDesign, Modeling, Synthesis and In Vitro Evaluation of new DPP-IV InhibitorsDesign, Modeling, Synthesis and In Vitro Evaluation of new DPP-IV InhibitorsAhmedMehannaDepartment of Pharmaceutical Sciences School of Pharmacy MCPHS University 179 Longwood Avenue Boston Ma 02115 USA Editor* E-mail: ahmed.mehanna@mcphs.edu
The authors have declared that no competing interests exist.
20181901201831JMCT-17-RA-171219102017170120182018Creative Commons Attribution LicenseThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. nbsp emsp emsp Dipeptidyl peptidase-IV enzyme is one of the targets for drug design to compact type-2 diabetes The current research addresses the design modeling synthesis and in vitro testing of potential new DPP-IV inhibitors X-ray structure of Sitagliptin with DPP-IV indicated hydrophobic interaction of the triazolo-piperazine ring system with the S2 pocket through the amino acid Phe357 Using molecular modeling we designed new compounds with better hydrophobic properties facing Phe357 Six compounds were designed docked synthesized and tested for DPP-IV inhibitory activity All designed compounds showed comparable affinity to the catalytic site of the enzyme to that of the standard drug however the activity as inhibitors as reflected by the IC50 range of 0 3 mu M ndash 1 3 mu M was lower than that of Sitagliptin IC50 22 nM The most active compound in the new series with IC50 of 0 3 mu M showed interesting a flipped over docking mode that is different from all other compounds including Sitagliptin with the lipophilic area directed away from the amino acid Phe357 The forces of interaction of the most active compound with the enzyme catalytic site were determined from modeling studies binding can be optimized by further structural modifications 10