ADAGRASIB (MRTX849) ANALOGLARININ YAPI TEMELLI OPTİMİZASYONU: KRAS G12D İNHİBİTÖR TASARIMI İÇİN GELİŞMİŞ HESAPLAMALI ÇERÇEVE

Abstract

KRAS G12D mutasyonu, özellikle mevcut tedavi seçeneklerinin sınırlı olduğu pankreas ve kolorektal kanserlerde önemli bir terapötik zorluk oluşturmaktadır. KRAS G12C mutasyonu için kovalent inhibitörler klinik başarıya ulaşmış olsa da, G12D’yi hedefleyen etkili ajanların geliştirilmesi yapısal ve biyokimyasal farklılıklar nedeniyle güçtür. Bu çalışma, KRAS G12D’yi hedefleyen adagrasib analoglarının yapı temelli optimizasyonu için bir hesaplamalı çerçeve sunmaktadır. Gelişmiş Moleküler Tasarım Platformu kullanılarak, 17–25 pozisyonlarındaki R-gruplarının ilaç kimyası odaklı değiştirilmesiyle elli türev tasarlanmıştır. KRAS G12D (PDB: 7RPZ) üzerinde yapılan moleküler kenetlenme analizleri, adagrasib’e (−7.7 kcal/mol) kıyasla daha güçlü bağlanan adaylar (−6.9 ila −9.6 kcal/mol) belirlemiştir. Yapı-aktivite analizinde 17. pozisyondaki izopropil grubunun en uygun olduğu ve Deriv-34’ün ARG-68, GLU-62 ve TYR-96 ile etkileşimler üzerinden en yüksek bağlanma gücünü (−9.6 kcal/mol) gösterdiği saptanmıştır. Temel bileşen analizi, hidroksillenmiş türevlerin daha yüksek ilaç benzerliği (QED = 0.384) ve sentez kolaylığına sahip olduğunu ortaya koymuştur. Kapsamlı ADME değerlendirmesiyle adayların önceliklendirilmesi, KRAS G12D inhibitör tasarımı için rasyonel bir yol haritası sunmaktadır.

Keywords

• KRAS G12D mutasyonu
• Adagrasib analogları
• Moleküler kenetlenme
• İlaç-benzerliği
• Hedefe yönelik kanser tedavisi

STRUCTURE-BASED OPTIMIZATION OF ADAGRASIB (MRTX849) ANALOGUES: ADVANCED COMPUTATIONAL FRAMEWORK FOR KRAS G12D INHIBITOR DESIGN

Abstract

The KRAS G12D mutation poses a major therapeutic challenge, particularly in pancreatic and colorectal cancers where current treatments are limited. While covalent inhibitors for KRAS G12C have reached clinical success, developing effective G12D-targeted agents remains difficult due to its unique structural and biochemical features. This study introduces a computational framework for structure-based optimization of adagrasib analogues targeting KRAS G12D. Using an Advanced Molecular Design Platform, fifty derivatives were designed by modifying positions 17–25 of the tetracyclic scaffold with medicinal chemistry-guided R-group substitutions. Molecular docking against KRAS G12D (PDB: 7RPZ) identified several high-affinity candidates (−6.9 to −9.6 kcal/mol) outperforming adagrasib (−7.7 kcal/mol). Structure–activity analysis revealed isopropyl substitution at position 17 as optimal, with Deriv-34 achieving the strongest binding (−9.6 kcal/mol) via key interactions with ARG-68, GLU-62, and TYR-96. Principal component analysis highlighted hydroxylated derivatives with superior drug-likeness (QED = 0.384) and synthetic feasibility. Comprehensive ADME profiling guided lead prioritization, defining a rational pipeline for KRAS G12D inhibitor design. This integrated computational approach provides a promising foundation for experimental validation and advances targeted therapy development against KRAS-driven cancers.

Keywords

• KRAS G12D Mutation
• Adagrasib analogues
• Molecular docking
• Drug-likeness
• Targeted cancer therapy

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