Multi-Constrained Evolutionary Molecular Design Framework: An Interpretable Drug Design Method Combining Rule-Based Evolution and Molecular Crossover

TL;DR

MCEMOL addresses the challenge of designing drug‑like molecules with chemical validity, interpretability, and efficiency by introducing a dual‑layer evolutionary framework that evolves both transformation rules and molecular structures. It combines a Rule Representation System with a Multidimensional Constraint System and seven molecular crossover strategies, guided by ATLAS‑DMPNN predictions and a composite fitness function F(m) = ∑_u w_u · S_u(m). The framework yields 100% molecular validity, high novelty and scaffold diversity, and strong drug‑likeness compliance while providing interpretable design pathways through evolving rules. Practically, MCEMOL bridges interpretable AI with practical molecule generation, enabling efficient exploration of chemical space from modest seeds without large datasets or extensive training.

Abstract

This study proposes MCEMOL (Multi-Constrained Evolutionary Molecular Design Framework), a molecular optimization approach integrating rule-based evolution with molecular crossover. MCEMOL employs dual-layer evolution: optimizing transformation rules at rule level while applying crossover and mutation to molecular structures. Unlike deep learning methods requiring large datasets and extensive training, our algorithm evolves efficiently from minimal starting molecules with low computational overhead. The framework incorporates message-passing neural networks and comprehensive chemical constraints, ensuring efficient and interpretable molecular design. Experimental results demonstrate that MCEMOL provides transparent design pathways through its evolutionary mechanism while generating valid, diverse, target-compliant molecules. The framework achieves 100% molecular validity with high structural diversity and excellent drug-likeness compliance, showing strong performance in symmetry constraints, pharmacophore optimization, and stereochemical integrity. Unlike black-box methods, MCEMOL delivers dual value: interpretable transformation rules researchers can understand and trust, alongside high-quality molecular libraries for practical applications. This establishes a paradigm where interpretable AI-driven drug design and effective molecular generation are achieved simultaneously, bridging the gap between computational innovation and practical drug discovery needs.

Figures (4)

• Figure 1: MCEMOL's overall architecture.
• Figure 2: Examples of molecular mutations.
• Figure 3: Molecular crossover engine.
• Figure 4: Trend diagram of basic chemical properties.