ALZHEIMER'S ASSOCIATION
AAIC 26

AI-Driven Physicochemical Optimization of Allosteric NAMPT Modulators:
From Generative Chemistry to Brain-Penetrant Therapeutics
David Scott Lewis, Enrique Zueco, Haley Yi
AIXC Bio, Zaragoza, Spain | reports@aixcbio.com

1 INTRODUCTION: THE NAD+ SALVAGE & NEUROPROTECTION CHALLENGE

Blood-Brain Barrier
NAD+ -> NAMPT -> NAD+

- Enhancing cellular NAD+ protects neurons
- Early scaffolds face CNS challenges
- Designing safe, brain-penetrant NAMPT PAMs requires navigating strict constraints
- Enhance cellular NAD+ in the NAD+ salvage pathway

2 METHODS: AI-DRIVEN GENERATIVE OPTIMIZATION PIPELINE

Data Input
Deep Learning Architecture
Source -> Deep Learning Architecture -> Predict BBB Permeability -> Medicinal Chemistry Profiling -> NAMPT highlights its rear-channel binding pocket, generative chemistry is structurally constrained -> Central Nervous System Multiparameter Optimization (CNS-MPO) -> Generative Chemistry and Improve
Molecular -> Evolve -> Improve

3 RESULTS: OVERCOMING DEVELOPABILITY HURDLES WITH HIGH-PERFORMANCE CANDIDATES

Strong Correlation: In Silico Prediction vs Experimental Validation
(Scatter plot: Central Nervous System Permeability vs Experimental Validation)

AI Pipeline: Generate Optimized Library of CNS-penetrant Candidates
(Histogram: Propensity vs Experimental Validation)

Prioritized Compound Bound to NAMPT
(Molecular structure image)

Overcoming Specific Developability Hurdles
(Molecular structure image)

Increased Cellular NAD+
(Bar chart showing NAD+ levels)

Cell Viability (No Cytotoxicity)
(Bar chart showing Cell Viability for NAD+, NAMPT)

4 CONCLUSIONS: ACCELERATED DISCOVERY OF CNS-PENETRANT NAMPT LEAD COMPOUNDS

Inherent Cellular Bioavailability and NAMPT Permeability
Deep Learning for BBB Permeability
Structure-Based Drug Design
Brain-Penetrant NAMPT Lead Compounds

- Rapid acceleration
Synthesized via deep learning for BBB permeability
- Developable compounds
Fine-tuned brain-penetrant NAMPT lead compounds
- Viable CNS delivery
Structure-guided brain-penetrant NAMPT modulators
- Strong neuroprotection
Strong neuroprotection without cytotoxicity

KEY TAKEAWAY: An integrated computational medicinal chemistry approach dramatically accelerates the discovery of brain-penetrant NAMPT modulators for neuroprotection, bridging developable lead compounds with viable CNS delivery.