Publication: In silico characterization of the klebsiella pneumoniae tetrahydrodipicolinate n-succinyl transferase enzyme and identification of potential inhibitors
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05/07/2023
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Abstract
KLEBSIELLA PNEUMONIAE TETRAHİDRODİPİKOLİNAT N-SÜKSİNİLTRANSFERAZ ENZİMİNİN İN SİLİKO KARAKTERİZASYONU VE POTANSİYEL İNHİBİTÖRLERİN TESPİTİAntimikrobiyal direnç (AMR), acil tedavi geliştirilmesi gereken küresel bir sağlık sorunudur. Bitkilere ve bakterilere özgü lizin biyosentez yolağının inhibe edilmesi memelilerde en az yan etkiye neden olacağı için yeni antibiyotik tasarımı açısından uygundur. İlaç geliştirilmesi için gereken süre ve maliyet gözönüne alındığında ilaç yeniden hedefleme yöntemlerinin kullanımı ve geliştirilmesi gelecek vadeden bir stratejidir. Bu tez çalışmasında dirençli bir bakteri türü olan Klebsiella Pneumoniae lizin biyosentez yolağının inhibisyonu çalışılmıştır. Bu yolakta önemli olan tetrahidrodipikolinat N-süksiniltransferaz (DapD) enzimi hedef olarak seçilmiştir. Enzimin bilinen bir üç boyutlu yapısı bulunmadığından dolayı bir homoloji modeli oluşturumuş ve valide edilmiştir. Bu model yüksek hacimli sanal tarama yöntemi kullanılarak 5903 adet onaylı ve deneysel ilaç molekülleri içeren bir ilaç kütüphanesine karşı taranmıştır. 6 tanesi onaylanmış olmak üzere 18 potansiyel yeniden hedefleme adayı keşfedildi. Enzimin koenzim A ile 150 ns moleküler dinamik simülasyonu ve doking sonuçlarına göre en iyi iki ligand ile 150 ns moleküler dinamik simülasyonları yapıldı. Ligandlar ile enzimin aktif bölgesi arasındaki etkileşimler analiz edildi ve değerlendirdi. Bu in siliko çalışma sonucunda, alendronat ve alfa-fosforibosilpirofosforik asit, Klebsiella pneumoniae enfeksiyonlarına yönelik umut verici aday antibakteriyel bileşikler olarak tespit edilmişitr. Bu iki bileşiği daha ileri deneysel testler için önermekteyiz.
ABSTRACTIN SILICO CHARACTERIZATION OF THE KLEBSIELLA PNEUMONIAE TETRAHYDRODIPICOLINATE N-SUCCINYL TRANSFERASE ENZYME AND IDENTIFICATION OF POTENTIAL INHIBITORS Antimicrobial resistance (AMR) is a global health concern that requires urgent development of new antibiotics. Targeting the lysine biosynthesis pathway, which is unique to plants and bacteria, offers promise for designing novel antibiotics without affecting the amino acid biosynthesis pathway in mammals. Drug repurposing is important due to the challenges in developing new drugs and the rise of drug-resistant bacteria. In this thesis, we focused on a resistant bacterium Klebsiella Pneumoniae and chose a drug target, tetrahydrodipicolinate N-succinyltransferase (DapD) enzyme, in its lysine biosynthesis pathway which is vital for the organism. No resolved structure of this enzyme was present hence a homology model was constructed and validated. Using a virtual screening method, we screened the model against a library of 5903 compounds including approved and investigational drugs. 18 potential repurposing candidates were discovered 6 of which are approved drugs. 150 ns molecular dynamics simulation for the enzyme-CoA complex was conducted. Additionally, the same simulation was conducted for the top two ligands. The interactions between the ligands and the active site of the enzyme were analyzed and evaluated. Based on these in silico study, alendronate and alpha-phosphoribosylpyrophosphoric acid were found to be the promising candidates for antibacterial activity against Klebsiella pneumoniae infections. We propose these two compounds for further experimental testing.
ABSTRACTIN SILICO CHARACTERIZATION OF THE KLEBSIELLA PNEUMONIAE TETRAHYDRODIPICOLINATE N-SUCCINYL TRANSFERASE ENZYME AND IDENTIFICATION OF POTENTIAL INHIBITORS Antimicrobial resistance (AMR) is a global health concern that requires urgent development of new antibiotics. Targeting the lysine biosynthesis pathway, which is unique to plants and bacteria, offers promise for designing novel antibiotics without affecting the amino acid biosynthesis pathway in mammals. Drug repurposing is important due to the challenges in developing new drugs and the rise of drug-resistant bacteria. In this thesis, we focused on a resistant bacterium Klebsiella Pneumoniae and chose a drug target, tetrahydrodipicolinate N-succinyltransferase (DapD) enzyme, in its lysine biosynthesis pathway which is vital for the organism. No resolved structure of this enzyme was present hence a homology model was constructed and validated. Using a virtual screening method, we screened the model against a library of 5903 compounds including approved and investigational drugs. 18 potential repurposing candidates were discovered 6 of which are approved drugs. 150 ns molecular dynamics simulation for the enzyme-CoA complex was conducted. Additionally, the same simulation was conducted for the top two ligands. The interactions between the ligands and the active site of the enzyme were analyzed and evaluated. Based on these in silico study, alendronate and alpha-phosphoribosylpyrophosphoric acid were found to be the promising candidates for antibacterial activity against Klebsiella pneumoniae infections. We propose these two compounds for further experimental testing.
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Keywords
DapD, Klebsiella pneumoniae, Tetrahidrodipikolinat N-süksiniltransferaz, Antimikrobiyal direnç, L-lizin biyosentez yolağı, Homoloji modelleme, İlaç yeniden konumlandırma
DapD, Klebsiella pneumoniae, Tetrahydrodipicolinate N-succinyltransferase, Antimicrobial resistance, L-lysine biosynthesis, Homology modeling, Drug repurposing