# Moldrug algorithm for an automated ligand binding site exploration by 3D aware molecular enumerations

## TL;DR

Moldrug is a new tool that helps design drug molecules by exploring chemical space and optimizing for binding affinity and drug-like properties.

## Contribution

Moldrug introduces a novel algorithm combining CReM library modifications and a genetic algorithm for automated ligand binding site exploration.

## Key findings

- Designed new potential SARS-CoV-2 MPro inhibitors with high predicted binding affinities.
- Moldrug-generated molecules showed high chemical diversity and synthetic accessibility.
- Predicted affinities as low as -10 kcal/mol were achieved using MM/GBSA and alchemical methods.

## Abstract

We present Moldrug, a computational tool for accelerating the hit-to-lead phase in structure-based drug design. Moldrug explores the chemical space using structural modifications suggested by the CReM library and by optimizing an adaptable fitness function with a genetic algorithm. Moldrug is complemented by Moldrug-Dashboard, a cross-platform and user-friendly graphical interface tailored for the analysis of Moldrug simulations. To illustrate Moldrug, we designed new potential inhibitors targeting the main protease (MPro) of SARS-CoV-2 by optimizing a consensus fitness function that balances binding affinity, drug-likeness, and synthetic accessibility. The designed molecules exhibited high chemical diversity. A subset of the designed molecules were ranked using MM/GBSA and alchemical binding free energy calculations, revealing predicted affinities as low as \documentclass[12pt]{minimal}
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\begin{document}$$-10\,~\hbox {kcal}\,\hbox {mol}^{-1}$$\end{document}-10kcalmol-1. Moldrug is distributed as a Python package under the Apache 2.0 license. It offers pre-configured multi-parameter fitness functions for molecular design, while being highly adaptable for integrating functionalities from external software. Documentation and tutorials are available at https://moldrug.rtfd.io.

The online version contains supplementary material available at 10.1186/s13321-025-01022-3.

Moldrug is a modular and flexible open-source framework for efficient exploration of the chemical space without need of prior training. We demonstrated the applicability of Moldrug by designing new potential inhibitors for the MPro of SARS-CoV-2 with high predicted affinity according to alchemical free energy calculations. Moldrug follows good coding practice and is accompanied by detailed documentation, making Moldrug an accessible and adaptable resource for cheminformatics research.

The online version contains supplementary material available at 10.1186/s13321-025-01022-3.