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

Authors : Ayşegül Varol

Pages : 135-144

Doi:10.22531/muglajsci.1826880

View : 29 | Download : 341

Publication Date : 2025-12-31

Article Type : Research Paper

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 mutasyonu, Adagrasib analogları, Moleküler kenetlenme, İlaç-benzerliği, Hedefe yönelik kanser tedavisi

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