Terapötik Hedef Enzimlerde (MAO, LOX, COX, ACE, Üreaz) Erişim Tünelleri ve Ligand Çıkış Yollarının Haritalanması: Doğal Ürün Kaynaklı İnhibitörlere Odaklanan Sistematik Bir Derleme

Ayşenur Özer; Zafer Ömer Özdemir

doi:10.53445/batd.1931307

TR EN

Terapötik Hedef Enzimlerde (MAO, LOX, COX, ACE, Üreaz) Erişim Tünelleri ve Ligand Çıkış Yollarının Haritalanması: Doğal Ürün Kaynaklı İnhibitörlere Odaklanan Sistematik Bir Derleme

Öz

Amaç: Bu sistematik derlemenin amacı; terapötik açıdan önemli beş enzimde (monoamin oksidaz [MAO], lipoksijenaz [LOX], siklooksijenaz [COX], anjiyotensin dönüştürücü enzim [ACE] ve üreaz) substrat/inhibitör erişim tünellerinin hesaplamalı haritalanmasına ilişkin literatürü PRISMA kılavuzu çerçevesinde sistematik olarak değerlendirmek ve tünel geometrisi ile doğal ürün kaynaklı inhibitörlerin bağlanma kinetiği arasındaki korelasyonu ortaya koymaktır. Gereç ve Yöntem: Sistematik tarama; PubMed, Scopus, Web of Science ve Google Scholar veri tabanlarında, 1 Ocak 2000 ile 31 Mart 2025 tarihleri arasında yayımlanan İngilizce ve Türkçe makaleleri kapsayacak şekilde gerçekleştirilmiştir. Arama stratejisi; hedef enzim adları (MAO, LOX, COX, ACE, üreaz) ile “access tunnel”, “ligand egress”, “CAVER”, “molecular dynamics”, “natural product inhibitor” ve “bottleneck” anahtar kelimelerinin Boolean operatörleri kullanılarak kombinasyonlarından oluşturulmuştur. Çalışma sürecinde PRISMA 2020 kontrol listesine tam uyum sağlanmıştır. Birincil arama kriterlerine ek olarak, tartışma bölümünde ele alınan Anadolu tıbbi bitkilerine dair spesifik literatür, genel doğal ürün inhibitörleri taraması içerisinden manuel olarak sınıflandırılmış ve analize dahil edilmiştir. Bulgular: Toplam 2.847 kayıt taranmış ve kriterlere uygun 89 çalışma dahil edilmiştir. İncelenen tüm enzimlerin 1,2–2,3 Å aralığında darboğaz yarıçapına sahip dinamik kapılı tünelleri olduğu belirlenmiştir. Doğal ürün inhibitörlerinin (kurkumin, kuersetin, berberin, baikalein, harmalin, gingerol, oleuropein, allisin, AKBA, resveratrol) tünel geometrisi ile uyumlu farmakokinetik profiller sergilediği görülmüştür. Özellikle COX-2 enziminde; darboğaz yarıçapı ile kalış süresi arasında ters bir korelasyon (niteliksel bir ters ilişki) gözlenmiştir. Sonuç: Enzim erişim tünellerinin geometrik ve fizikokimyasal özellikleri, doğal ürün kaynaklı inhibitörlerin etkinliğini doğrudan etkilemektedir. Bu sistematik derleme, bütünleyici tıp perspektifinden hesaplamalı enzimoloji ile fitoterapi arasında moleküler bir köprü kurarak, geleneksel tıpta kullanılan bitkisel bileşiklerin etki mekanizmalarına açıklama getirmektedir.

Anahtar Kelimeler

Erişim tüneli , ligand çıkış yolu , darboğaz yarıçapı , moleküler dinamik , CAVER , doğal ürün inhibitörü , fitoterapi

Mapping Access Tunnels and Ligand Egress Pathways in Therapeutic Target Enzymes (MAO, LOX, COX, ACE, Urease): A Systematic Review Focusing on Natural Product-Derived Inhibitors

Abstract

Objective: The objective of this systematic review is to comprehensively examine the research regarding the computational mapping of the substrate/inhibitor access tunnels of five critical therapeutic enzymes: monoamine oxidase (MAO), lipoxygenase (LOX), cyclooxygenase (COX), angiotensin-converting enzyme (ACE), and urease. It also wants to talk about how the shape of the tunnel affects how quickly natural product-derived inhibitors stick to things. Materials and Methods: We systematically searched the PubMed, Scopus, Web of Science, and Google Scholar databases for English and Turkish articles published between January 1, 2000, and March 31, 2025. The search strategy used combinations of target enzyme names and keywords like "access tunnel," "ligand egress," "CAVER," "molecular dynamics," "natural product inhibitor," and "bottleneck," all linked together by Boolean operators. The study strictly followed the PRISMA 2020 checklist. Along with the main search criteria, some literature about Anatolian medicinal plants that was mentioned in the synthesis was manually sorted from the general natural product inhibitor pool and added to the analysis. Results: Of the 2,847 records examined, 89 satisfied the inclusion criteria. We found that all the enzymes examined had tunnels that underwent conformational changes and exhibited bottleneck radii ranging from 1.2 to 2.3 Å. The pharmacokinetic characteristics of natural product inhibitors such as curcumin, quercetin, berberine, baicalein, harmaline, gingerol, oleuropein, allicin, AKBA, and resveratrol corresponded to the configurations of tunnels. A significant negative association was observed between the bottleneck radius and residency duration, especially for the COX-2 enzyme. Conclusion: The configuration and the physical and chemical characteristics of enzyme access tunnels directly influence the efficacy of inhibitors derived from natural products. From an integrative medicine point of view, this systematic review connects computational enzymology and phytotherapy on a molecular level. It also explains how herbal compounds used in traditional medicine work at a structural level.

Keywords

Access tunnel , ligand egress , bottleneck radius , molecular dynamics , CAVER , natural product inhibitor , phytotherapy

References

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Details

Primary Language

Turkish

Subjects

Bioengineering (Other)

Journal Section

Systematic Reviews and Meta Analysis

Authors

Ayşenur Özer
0009-0009-4034-9841
Türkiye

Zafer Ömer Özdemir ^*
0000-0002-8362-3136
Türkiye

Publication Date

April 28, 2026

Submission Date

April 15, 2026

Acceptance Date

April 22, 2026

Published in Issue

Year 2026 Volume: 7 Number: 1

DOI

https://doi.org/10.53445/batd.1931307

IZ

https://izlik.org/JA28UJ78XX

APA

Özer, A., & Özdemir, Z. Ö. (2026). Terapötik Hedef Enzimlerde (MAO, LOX, COX, ACE, Üreaz) Erişim Tünelleri ve Ligand Çıkış Yollarının Haritalanması: Doğal Ürün Kaynaklı İnhibitörlere Odaklanan Sistematik Bir Derleme. Journal of Integrative and Anatolian Medicine, 7(1), 34-45. https://doi.org/10.53445/batd.1931307

J. Integr. Anatol. Med. (Abbreviated Title)

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Terapötik Hedef Enzimlerde (MAO, LOX, COX, ACE, Üreaz) Erişim Tünelleri ve Ligand Çıkış Yollarının Haritalanması: Doğal Ürün Kaynaklı İnhibitörlere Odaklanan Sistematik Bir Derleme

Öz

Anahtar Kelimeler

Mapping Access Tunnels and Ligand Egress Pathways in Therapeutic Target Enzymes (MAO, LOX, COX, ACE, Urease): A Systematic Review Focusing on Natural Product-Derived Inhibitors

Abstract

Keywords

References

Details

Primary Language

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Journal Section

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Acceptance Date

Published in Issue

DOI

IZ

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J. Integr. Anatol. Med. (Abbreviated Title)