Shape and color: A unifying principle for modeling molecules

Shape and color: A unifying principle for modeling molecules.
May 2025 by Paul Hawkins, Ph.D.

Abstract:
The search for an even somewhat widely applicable description of molecular structure, properties, and interactions has been ongoing for decades, and many possible solutions have been proposed. Treating molecules as atoms and bonds and assessing their interactions with forcefields continues to be widely used, as it is both a relatively simple representation and has low computational demands. Modeling molecules as nuclei and electrons, using electronic structure methods to calculate interactions, is more physically realistic but much more computationally demanding.

This talk will discuss representing molecules in an extremely simple way - as a shape with embedded chemical features, or color - to calculate both properties and interactions. This approach carries the appealing conceptual simplicity of forcefields, while being orders of magnitude faster for some applications. We will illustrate the power of the shape and color representation with successful applications across a wide range of tasks in computational drug discovery: target validation, binding site plasticity, virtual screening (both ligand-based and structure-based), and affinity prediction with machine learning.

Timestamps:
[00:00] – Introduction and Overview of Drug Discovery
[01:18] – Shape and Electrostatics: A Modeling Framework
[06:02] – Tanimoto Combo: A Metric for Molecular Similarity
[10:21] – Hybrid Docking: Enhancing Speed and Accuracy
[17:01] – Shape-Based Ligand Fitting into Electron Density
[31:59] – Molecular Whiskey: Knowledge-Distilled Virtual Screening

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