Publication: Investigation of the effects of novel azole compounds on the activity of mPGES-1 enzyme
Abstract
Mikrozomal prostaglandin E2 sentaz-1 (mPGES-1) enziminin inhibisyonu, siklooksijenaz enzimlerin inhibisyonuyla ilişkilendirilen yan etkilerin görülmemesi sebebiyle yeni nesil steroid olmayan anti-enflamatuvar (SOAİ) ilaçların tasarımı için umut vaat etmektedir. Azol bileşikleri, azot içeren heterosiklik bileşiklerdir ve tıpta geniş bir kullanım alanına sahip olup, tıbbi kimyada umut vaat eden bileşikler olarak görülmektedir. Bu çalışmada, çeşitli bilgisayar-destekli ilaç tasarımı teknikleri bir arada kullanılmıştır. Çeşitli moleküler doking programları kullanılarak yapı-temelli sanal tarama gerçekleştirilmiştir. Farmakofor modeller oluşturulmuş ve en iyi modelin Güner-Henry skoru 0.89 olarak hesaplanmıştır. En iyi 10 aday azol bileşiğin bağlanmaları incelenmiş ve en iyi bağlanma gösteren (-8.38 kcal/ mol) bileşik üzerinde moleküler dinamik simülasyonları ile daha ileri incelemeler yapılmıştır. Böylece furazan1224 (ZINC001142847306) bileşiğinin substrat olan prostaglandin H2’nin (PGH2) bağlanma bölgesini işgal ettiği gözlemlenmiş ve 100 ns boyunca stabil kaldığı gözlenmiştir. Aktif bölgedeki daimi hidrojen bağları, furazan1224’ün simülasyon boyunca stabilitesini desteklemiştir. Farmakokinetik veriler furazan1224’ün sitokrom P450 3A4 enzimini inhibe etmek sonucu meydana gelen riskleri taşımadığını göstermiştir.
Inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is promising for designing novel non-steroidal anti-inflammatory drugs, as they lack side-effects associated with the inhibition of cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (-8.38 kcal/ mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZINC001142847306) occupied the binding site of the substrate, prostaglandin H2 (PGH2) and remained stable for 100 ns. Continuous hydrogen bonds with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.
Inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is promising for designing novel non-steroidal anti-inflammatory drugs, as they lack side-effects associated with the inhibition of cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (-8.38 kcal/ mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZINC001142847306) occupied the binding site of the substrate, prostaglandin H2 (PGH2) and remained stable for 100 ns. Continuous hydrogen bonds with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.