Research Areas


We focus on the following areas:

  • Small-molecule conformer generation, including complex macrocycles
  • Molecular docking and protein binding site comparison and analysis
  • Three-dimensional molecular similarity and multiple ligand alignment
  • Prediction of affinity and pose for biologically interesting molecules

Our approach to predictive modeling is different because we respect physics, chemistry, and biology while also taking machine learning and parameter optimization seriously.

Tools Module: ForceGen methodology

Docking Module: Virtual screening and highly accurate pose prediction

Similarity Module: eSim method for virtual screening and multiple ligand alignment

Affinity Module: Machine learning using QuanSA

What’s New?


JCIM: Improvements in Docking
April 9, 2020

The latest improvements in Surflex-Dock, especially with respect to virtual screening, has been published in a special issue of JCIM. Ensemble docking is shown to produce much better results than single-structure docking on the DUD-E+ benchmark. Ligand-based methods employing eSim are shown to be competitive as well. Hybrid approaches are much better than single-mode approaches.

JCAMD: The eSim  Similarity Method
October 24, 2019

We have published, with Stephen Johnson, a new 3D molecular similarity method (called eSim) that directly incorporates Coulombic field comparison with surface-shape and hydrogen-bonding comparison. It is both faster and more accurate that commonly used alternatives, both for virtual screening and pose prediction. The paper is entitled “Electrostatic-field and surface-shape similarity for virtual screening and pose prediction.”

JMC: xGen Real-Space Ligand Refinement
September 2, 2020

We have published a paper with colleagues from Merck entitled “XGen: Real-Space Fitting of Complex Ligand Conformational Ensembles to X‐ray Electron Density Maps.” We show that conformational ensembles, without atom-specific B-factors, are better models for ligands in terms of both fit to X-ray density and strain energy. Ligand refinement is demonstrated on a large set of macrocycles, and de novo fitting is demonstrated on a set of non-macrocyclic small molecules.  The xGen approach offers a new paradigm for ligand modeling within X-ray diffraction data.

JCAMD: QuanSA Affinity Prediction Method
June 18, 2018

Our paper describing the new QuanSA approach (Quantitative Surface-Field Analysis) has been published. The method offers a novel mutliple-instance machine-learning method for binding affinity and pose prediction. It is applicable in cases where ligand structure and activity data are available either with or without a crystallographic structure of the protein target. The method is competitive with the FEP approach when structures are available, and the methods have uncorrelated errors, resulting in improved predictions using the approaches in combination.