PHARMACOPHORE MODELING STUDIES ON KNOWN MMP-9 ENZYME INHIBITORS TO IDENTIFY THE IMPORTANT COMMON FEATURES

Year 2020, Volume: 44 Issue: 2, 204 - 210, 31.05.2020

Tugba Ertan-bolelli , Kayhan Bolelli

https://doi.org/10.33483/jfpau.690373

Cited By: 1

Abstract

Objective: In this study, pharmacophore models were generated to explain the structure–activity relationships by using the known MMP-9 inhibitors.
Material and Method: Pharmacophore models were generated to explain the specification of the structure–activity relationships of common pharmacophoric sites of the known MMP-9 inhibitors. For this study Discovery Studio 3.5 software was used. A set of known MMP-9 inhibitors (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A, and Ro32-3555) were used for common feature pharmacophore generation method. Selected hypothesis included two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature.
Result and Discussion: All of the tested inhibitors except CGS-27023A and Ro32-3555 fitted the selected pharmacophore model perfectly. These two inhibitors did not fit the A2 feature. It can be concluded that A1, D1, and H1 features at the given positions could be necessary for the activity. Additionally, we compared the pharmacophore model with NFH and MMP-9 enzyme complex to identify the important interactions. At the given positions of all of the pharmacophoric features, there is an interaction with the protein. This is also supported our pharmacophore hypothesis. As a result, this pharmacophore model could be useful to design new small molecule inhibitors of MMP-9 enzyme.

Keywords

cancer, inflammatory diseases, MMP-9, pharmacophore modeling, structure–activity relationships

ÖNEMLİ ORTAK ÖZELLİKLERİ TANIMLAMAK AMACIYLA, BİLİNEN MMP-9 ENZİM İNHİBİTÖRLERİ ÜZERİNDE YAPILAN FARMAKOFOR MODELLEME ÇALIŞMALARI

Abstract

Amaç: Bu çalışmada, yapı-aktivite ilişkilerini açıklamak amacıyla bilinen MMP-9 inhibitörleri üzerinden farmakofor modeller oluşturuldu.
Gereç ve Yöntem: Bilinen MMP-9 inhibitörlerinin ortak farmakoforik özellikleri belirlenerek, yapı-aktivite ilişkilerini açıklamak üzere farmakofor modeller oluşturuldu. Bu çalışma için Discovery Studio 3.5 programı kullanıldı. Bilinen MMP-9 inhibitörleri (NFH, Batimastat, Marimastat, Prinomastat, CGS-27023A ve Ro32-3555), ortak farmakofor özelliklerin belirlenmesinde kullanıldı. İki hidrojen bağı alıcısı, bir hidrojen bağı donörü ve bir hidrofobik özellik içeren hipotez seçildi.
Sonuç ve Tartışma: CGS-27023A ve Ro32-3555 dışındaki test edilen tüm inhibitörler, seçilen farmakofor modele mükemmel bir şekilde uydu. Bu iki inhibitör A2 özelliğine uymadı. Buna göre, etki için verilen konumlardaki A1, D1 ve H1 özelliklerinin gerekli olabileceği sonucuna varıldı. Ayrıca, önemli etkileşimleri tanımlamak için farmakofor model, NFH ve MMP-9 enzim kompleksi ile karşılaştırıldı. Tüm farmakoforik özelliklerin verilen pozisyonlarda, protein ile bir etkileşim gözlendi. Bu durum farmakofor hipotezimizi de desteklemektedir. Sonuç olarak, bu farmakofor model, MMP-9 enziminin yeni küçük molekül inhibitörlerini tasarlamak için yararlı olabilir.

Keywords

enflamatuar hastalıklar, farmakofor modelleme, kanser, MMP-9, yapı-etki ilişkileri

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