Optimizing blood-brain barrier permeability in KRAS inhibitors:A structure-constrained molecular generation approach
10.1016/j.jpha.2025.101337
- Author:
Xia SHENG
1
;
Yike GUI
;
Jie YU
;
Yitian WANG
;
Zhenghao LI
;
Xiaoya ZHANG
;
Yuxin XING
;
Yuqing WANG
;
Zhaojun LI
;
Mingyue ZHENG
;
Liquan YANG
;
Xutong LI
Author Information
1. Drug Discovery and Design Center,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica Chinese Academy of Sciences,Shanghai,201203,China;University of Chinese Academy of Sciences,Beijing,100049,China
- Publication Type:Journal Article
- Keywords:
KRAS inhibitors;
Drug design;
Blood-brain barrier permeability;
Molecular optimization;
Deep learning;
Generation models
- From:
Journal of Pharmaceutical Analysis
2025;15(8):1848-1859
- CountryChina
- Language:English
-
Abstract:
Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of thera-peutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucial for treating central nervous system(CNS)malignancies.Although molecular generation models have recently advanced drug discovery,they often overlook the complexity of bio-logical and chemical factors,leaving room for improvement.In this study,we present a structure-constrained molecular generation workflow designed to optimize lead compounds for both drug effi-cacy and drug absorption properties.Our approach utilizes a variational autoencoder(VAE)generative model integrated with reinforcement learning for multi-objective optimization.This method specifically aims to enhance BBB permeability(BBBp)while maintaining high-affinity substructures of KRAS in-hibitors.To support this,we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models.Additionally,we introduce two novel metrics,the knowledge-integrated reproduction score(KIRS)and the composite diversity score(CDS),to assess structural performance and biological relevance.Retrospective validation with KRAS inhibitors,AMG510 and MRTX849,demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications.This study provides a robust framework for accelerating the structural enhancement of lead compounds,advancing the drug development process across diverse targets.
