Publication: DPP4, α-amilaz ve α-glukosidaz enzimlerinin inhibisyonunu hedefleyen yeni heterosiklik bileşiklerin sentezi, in vitro ve in siliko çalışmaları
Abstract
DPP4, α-amilaz ve α-glukosidaz enzimlerinin inhibisyonunu hedefleyen yeni heterosiklik bileşiklerin sentezi, in vitro ve in siliko çalışmaları Tip 2 diyabet, insulin hormonunun yetmezliği veya etkinliğinin azalması sonucu ortaya çıkan; kan şekerinin yükselmesi ile ilişkili kronik bir hastalıktır. Diyabetli hasta sayısındaki artış hızı oral hipoglisemik ilaç piyasasını da hızla büyütmekte, diyabetin kontrolü için yeni ve daha az yan tesirli ajanların bulunmasını zorunlu kılmaktadır. Çalışmamızda heterosiklik halkaya sahip özgün maddeler sentezlenerek karakterize edilmiş ve dipeptidil peptidaz-4 (DPP4), α-amilaz ve α-glukosidaz enzimleri üzerindeki olası inhibisyon etkileri in siliko ve in vitro yöntemlerle incelenmiş ve inhibisyon aktiviteleri belirlenmiştir. Çalışmamızın in siliko kısmında sentezlenen bileşiklerin farmasötik olarak uygunluğu araştırılmış; moleküler yerleştirme yöntemi ile DPP4, α-amilaz ve α-glukosidaz enzimlerinin aktif bölgelerindeki amino asit etkileşimleri incelenmiş, bağlanma enerjileri bulunmuştur. Moleküler yerleştirme çalışmaları ile deneysel çalışmaların sonuçların birbirini destekleyip desteklemediği araştırılmıştır. İn siliko ve in vitro çalışmalarda bilinen DPP4 inhibitörlerinden biri olan sitaglipitin, literatürde en çok rastlanan α-amilaz inhibitörü olan akarboz, α-glukosidaz için ise kuarsetin, model olarak seçilmiştir. Bileşiklerin DPP-4 ve glukosidaz üzerinde kayda değer bir inhibisyon aktivitesine sahip olmadığı ancak (3a), (3d), (7) ve (7a)’nın dikkat çekici şekilde α-amilazı inhibe ettiği gözlemlenmiş olup; inhibisyon çalışmalarına ek olarak en iyi inhibisyonu veren bu dört bileşik ile in vitro ve in siliko yöntemler kullanılarak Sığır Serum Albümin (BSA) ile bağlanma çalışmaları yapılmıştır. BSA bağlanma çalışmalarının sonuçları değerlendirildiğinde bağlanmanın negatif ΔG değerine sahip olduğu hesaplanmış BSA ile 3a, 3d, 7 ve 7a bileşikleri arasındaki etkileşimlerin kendiliğinden gerçekleştiği sonucuna varılmıştır. Çalışmamız sonucunda yukarıda saydığımız bileşiklerin fonksiyonel grupları modifiye edilerek in vivo çalışmalarla desteklendiğinde Tip 2 diyabet hastalığı tedavisinde kullanılan ilaçlara alternatif olabilir ve yeni ilaçların geliştirilmesine katkıda bulunabilir.
Synthesis, in vitro, and in silico studies of novel heterocyclic compounds targeting the inhibition of DPP4, α-amylase, and α-glucosidase enzymes Type 2 diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The oral hypoglycemic drug market is expanding as the number of diabetic patients increases significantly. For the control of diabetes, the discovery of new antidiabetic agents with less side effects is obligatory. In this context, original compounds having heterocyclic structures were synthesized and characterized and thier inhibitory activities on Dipeptidyl peptidas-4 (DPP4), a-amylase and a-glucosidase were investigated by in silico and in vitro methods, and their inhibitory activities were expressed as IC50 values. In the in silico part of our study, pharmaceutical suitability of these unique compounds were analyzed, and thier interactions with amino acids at the active sites of DPP4, a-amylase and a-glucosidase were examined using molecular docking method and binding energies were also determined. It has been investigated whether the results of molecular docking studies and experimental studies support each other. In both in silico and in vitro studies, sitagliptin, which is one of the well known DPP4 inhibitors, acarbose and quercetin the most common inhibitors in literature; for α-amylase and α-glucosidase simultaneously were selected as model compounds. Compounds had no considirable inhibitory activity on DPP4 and α-glucosidase but it was observed that compounds; (3a), (3d), (7) and (7a) had the most remarkable α-amylase inhibitory activity; in addition to the inhibition studies, in vitro and in silico Bovine Serum Albumin (BSA) binding studies were performed with these four compounds. When the results of the BSA binding studies were evaluated, it was concluded that the binding had a negative ΔG value, indicating that the interactions between BSA and compounds 3a, 3d, 7 and 7a occurred spontaneously. In light of these findings, modifying the functional groups of these novel compounds and supporting them with in vivo studies may contribute to the development of new drugs for the treatment of Type 2 diabetes.
Synthesis, in vitro, and in silico studies of novel heterocyclic compounds targeting the inhibition of DPP4, α-amylase, and α-glucosidase enzymes Type 2 diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The oral hypoglycemic drug market is expanding as the number of diabetic patients increases significantly. For the control of diabetes, the discovery of new antidiabetic agents with less side effects is obligatory. In this context, original compounds having heterocyclic structures were synthesized and characterized and thier inhibitory activities on Dipeptidyl peptidas-4 (DPP4), a-amylase and a-glucosidase were investigated by in silico and in vitro methods, and their inhibitory activities were expressed as IC50 values. In the in silico part of our study, pharmaceutical suitability of these unique compounds were analyzed, and thier interactions with amino acids at the active sites of DPP4, a-amylase and a-glucosidase were examined using molecular docking method and binding energies were also determined. It has been investigated whether the results of molecular docking studies and experimental studies support each other. In both in silico and in vitro studies, sitagliptin, which is one of the well known DPP4 inhibitors, acarbose and quercetin the most common inhibitors in literature; for α-amylase and α-glucosidase simultaneously were selected as model compounds. Compounds had no considirable inhibitory activity on DPP4 and α-glucosidase but it was observed that compounds; (3a), (3d), (7) and (7a) had the most remarkable α-amylase inhibitory activity; in addition to the inhibition studies, in vitro and in silico Bovine Serum Albumin (BSA) binding studies were performed with these four compounds. When the results of the BSA binding studies were evaluated, it was concluded that the binding had a negative ΔG value, indicating that the interactions between BSA and compounds 3a, 3d, 7 and 7a occurred spontaneously. In light of these findings, modifying the functional groups of these novel compounds and supporting them with in vivo studies may contribute to the development of new drugs for the treatment of Type 2 diabetes.