YENİ TETRAHİDRONAFTALEN-BENZİMİDAZOL TÜREVİ BİLEŞİKLERİN MOLEKÜLER DOKİNG ÇALIŞMALARI VE ONLARIN ANTİ-MRSA AKTİVİTELERİNİN KARŞILAŞTIRILMASI

Year 2019, Volume: 43 Issue: 1, 20 - 27, 31.01.2019

Fikriye Zengin Mehmet Murat Kısla , Zeynep Ates Alagoz

Abstract

Amaç: Metisiline dirençli S. aureus
(MRSA), birçok antibiyotiğe karşı dirençli olup, özellikle hastane ortamında
mortaliteye neden olmaktadır. Önceden sentezlenmiş olan retinoidal bileşiklerin
MRSA üzerindeki inhibitor aktivitesini incelemek adına bu bileşiklerin QSAR
özellikleri hesaplanmış ve MRSA Pirüvat kinaz (PK) ile doking çalışmaları
gerçekleştirilmiştir.

        Gereç ve Yöntem: Başlangıçta, ligand hazırlama gerçekleştirilmiştir. Bileşiklerin
optimizasyonu için Hyperchem Professional kullanılmış, bu yazılımda Molecular
Mechanics Force Field (MMFF) ve semi-empirik metod uygulanmıştır. Ligand
dosyalarını pdb formatına dönüştürdükten sonra, yük ve torsiyon özellikleri
AutoDockTools 1.5.6 ile eklenmiştir. MRSA pirüvat kinaz makromolekül dosyası
(PDB ID: 3T07) protein data bank’tan alınmıştır. Bağlanma için uygun zincir
UCSF Chimera ile belirlenmiştir. Makromoleküle polar hidrojenler ve Gasteiger
yükleri AutoDockTools 1.5.6 ile eklenmiştir. Ligandın proteine bağlanma cebi,
protein data bank’taki protein-ligand kompleksinden yola çıkılarak tespit
edilmiştir. Retinoidal bileşiklerin MİK değerleri için Ates-Alagoz ve ark.
tarafından yapılmış olan çalışmaya başvurulmuştur.

         Sonuç
ve Tartışma: 1, 4, 5, 6, 7 numaralı bileşikler PK inhibitor
aktiviteleri en yüksek adaylar olarak seçilmiştir. Bu bileşikler, nispeten
düşük olan MİK değerlerine ek olarak önceden bildirilen PK inhibitörü aday
bileşiklere benzer bağlanma şekilleri göstermiştir. PK’nın iki monomerik
ünitesinde yer alan His365 ve Ile361 ile etkileşme, bu üniteler arasında bir
köprü oluşturmaktadır. Yapılan QSAR hesaplamasına göre, en aktif olan
bileşiklerde 1010 Å3’dan düşük moleküler hacim değerleri görülmektedir. Buna ek
olarak, log P’nin aktivite üzerinde bir etkiye sahip olmadığı görülmüştür. Bu bağlanma
şekli ve etkileşimler, söz konusu bileşiklerin MRSA Pirüvat kinaz’daki umut
verici inhibitor aktivitelerinin nedeni olabilir.

Keywords

Benzimidazol, doking, biyoinformatik, antibiyotikler, QSAR

MOLECULAR DOCKING STUDIES OF SOME TETRAHYDRONAPHTALENE-BENZIMIDAZOLE DERIVATIVES AND CORRELATION WITH THEIR CORRESPONDING ANTI-MRSA ACTIVITIES

Abstract

        Objective: Methicillin- resistant S. aureus (MRSA) is a type of
bacteria which is resistant to various types of antibiotics and causes
mortality in hospital environment and community. To further investigate the
inhibition activity of previously synthesized retinoidal compounds against
MRSA, docking studies of these compounds with MRSA pyruvate kinase (PK) were
made.

        Material and Method: As a first step, ligand preparation
procedure has been made. For optimization of compounds, Hyperchem Professional
was used. Molecular Mechanics Force Field (MMFF) and semi-empirical methods
have been implemented in this program. After converting the ligands to pdb
files, charges and torsions were added via AutoDockTools 1.5.6. Macromolecule
file for MRSA Pyruvate kinase (PDB ID:3T07) was procured from protein data
bank. Appropriate chain for binding was chosen via UCSF Chimera. Polar
hydrogens and Gasteiger charges were added to macromolecule via AutoDockTools
1.5.6. Gridbox has been predicted by protein- ligand complex which is currently
present in protein data bank and prepared via same software.  Docking process was made via AutoDock Vina.
For MIC values of retinoidal compounds, previous study by Ates-Alagoz et al.
has been used. In addition, some QSAR properties were calculated via Hyperchem
Professional and were also interpreted.

        Result and Discussion: Compounds 1, 4, 5,
6, 7 were selected for their PK inhibitor activities. Addition to their
relatively lower MIC values, they also show similar binding modes to previously
presented PK inhibitor candidates. Binding of compounds with His365 and Ile361
in both monomeric units of PK, creates a bridge that links these units. In
terms of QSAR, molecular volume below 1010 Å3 is favorable. Moreover, log P
does not have an impact on activity. This binding mode and interactions with
aminoacid residues may be the cause of their promising inhibition activity
against MRSA Pyruvate kinase.

Keywords

benzimidazoles, docking, bioinformatics, antibiotics, QSAR

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