Geometric deep reinforcement learning with hierarchical variational autoencoders for de novo drug design and activity optimization

Traditional drug discovery is a resource-intensive process with high attrition rates and the huge difficulty of working with a chemical space that is thought to include \(10^{60}\) molecules. Even though computational chemistry has come a long way, traditional generative models still use string-based representations like SMILES, which have trouble capturing intricate three-dimensional spatial interactions and often make structures that aren’t real. Moreover, current reinforcement learning methodologies frequently do not achieve an equilibrium between molecular diversity and high-affinity biological activity. To overcome these constraints, this research introduces an innovative integrated framework that merges Geometric Multi-Discrete Soft Actor-Critic (Geom-SAC) and Multi-stage Variational Autoencoders (MS-VAE) to improve de novo molecular creation and activity optimisation. The main new idea is the combination of geometric deep learning, which enforces physical atomic restrictions, and a hierarchical VAE architecture, which organises the latent space into manageable structural steps from scaffold formation to functional group optimisation. We also use a Non-Covalent Interaction-Aware (NCIA) graph neural network in our method to improve protein-ligand affinity predictions by simulating complex intermolecular forces. Experimental results on benchmark datasets, such as ZINC250k and PDBbind, show that the proposed framework improves binding affinity scores by 15% and the Valid-Unique-Novel (VUN) molecule ratio by 20% compared to the best existing methods. Also, adding a security layer based on blockchain technology makes sure that data is secure and can be tracked. This all-encompassing method provides a strong, highly accurate answer for next-generation AI-driven pharmacology. It greatly narrows the gap between computational design and experimental validation.