Methods of computer-aided drug design

Advancing the technologies of computer-aided drug design (CADD) is a central theme of our work.

We are developing advanced methods of computing protein-small molecule binding thermodynamics, as well as new ways to think about and model the role of water structure in protein-ligand binding.

One of the factors that limits the accuracy of CADD methods is the approximate character of the potential functions, or force fields, that are at the foundation of many molecular modeling technologies. We are therefore engaged in a number of projects aimed at improving the accuracy of force fields. One approach involves synthesizing host-guest systems, small molecular recognition systems that are conceptually similar to protein-drug systems but are much easier to study experimentally and simulate. They are thus powerful and informative tools to test and improve force fields and simulation methods in general. We are also an active member lab of the Open Force Field Initiative and the associated Consortium.

Selected Publications

Simulating water exchange to buried binding sites. I Ben-Shalom, C Lin, T Kurtzman, RC Walker, MK Gilson. J Chem Theo Comput 15:2684, 2019, 10.1021/acs.jctc.8b01284

Facile synthesis of a diverse library of mono-3-substituted beta-cyclodextrin analogues. K Kellett, BM Duggan, MK Gilson. Supramolec Chem 31:251, 2019, 10.1080/10610278.2018.1562191

Evaluating force field performance in thermodynamic calculations of cyclodextrin host–guest binding: Water models, partial charges, and host force field parameters. NM Henriksen, MK GIlson. J Chem Theo Comput 13:4253, 2017, 10.1021/acs.jctc.7b00359.

Attach-pull-release calculations of ligand binding and conformational changes on the first BRD4 bromodomain. G Heinzelman, NM Henriksen, MK Gilson. J Chem Theo Comput 13:3260, 2017, 10.1021/acs.jctc.7b00275.

Evaluation and minimization of uncertainty in ITC binding measurements: heat error, concentration error, saturation, and stoichiometry. SA Kantonen, NM Henriksen, MK Gilson. Biochim Biophys Acta Gen Subj 1861:485, 2017, 10.1016/j.bbagen.2016.09.002.

Grid inhomogeneous solvation theory: hydration structure and thermodynamics of the miniature receptor cucurbit [7] uril. CN Nguyen, T Kurtzman, MK Gilson. J Chem Phys 137:044101, 10.1063/1.4733951.

Blinded prediction challenges for CADD and molecular modeling technologies

An ongoing challenge in the field has been to objectively and systematically evaluate CADD methods. We address this by organizing blinded prediction challenges focused on protein-ligand binding, through the Drug Design Data Resource (D3R) project, and focused on simpler systems, such as host-guest binding, through the SAMPL project.

Selected Publications

Continuous Evaluation of Ligand Protein Predictions: A Weekly Community Challenge for Drug Docking. JR Wagner, CP Churas, S Liu, RV Swift, M Chiu, C Shao, VA Feher, SK Burley, MK Gilson, RE Amaro. Structure, 2019, in press (as of 4/25/2019).

D3R Grand Challenge 3: blind prediction of protein–ligand poses and affinity rankings. Z Gaieb, CD Parks, M Chiu, H Yang, C Shao, WP Walters, MH Lambert, N Nevins, SD Bembenek, MK Ameriks, T Mirzadegan, SK Burley, RE Amaro, MK Gilson. J Comput-Aided Drug Design 33:1, 2019, 10.1007/s10822-018-0180-4.

Overview of the SAMPL5 host–guest challenge: Are we doing better? J Yin, NM Henriksen, DR Slochower, MR Shirts, MW Chiu, DL Mobley, MK Gilson. J Comput-Aided Drug Design 31:1, 2017, 10.1007/s10822-016-9974-4.

Database of measured binding affinities

We created and continue to expand and improve BindingDB, the first public database of measured protein-small molecule binding data. This project collects data from scientific articles, patents, and related databases and makes it easy to search, browse, and download in machine-readable formats. BindingDB is used worldwide for projects in areas that include drug discovery and CADD methods development, as well as for education and clinical practice. As of 2019, BindingDB contains over 1.6 million data for over 700,000 small molecules and 7,000 proteins, and is collecting tens of thousands of data each year from US Patents.

Selected Publications

BindingDB in 2015: a public database for medicinal chemistry, computational chemistry and systems pharmacology. MK Gilson, T Liu, M Baitaluk, G Nicola, L Hwang, J Chong. Nucleic Acids Res 44: D1045, 2015, 10.1093/nar/gkv1072.

BindingDB: a web-accessible database of experimentally determined protein–ligand binding affinities. T Liu, Y Lin, X Wen, RN Jorissen, MK Gilson. Nucleic Acids Res 35:D198, 2006, 10.1093/nar/gkl999.

Theory and modeling of molecular motors and systems out of equilibrium

We are also interested in learning ways that nonequilibrium statistical mechanics plays out at the molecular and perhaps cellular levels and are interested in fundamentals and design principles of molecular motors and of driven molecular motions.

Selected publications

Motor-like properties of nonmotor enzymes. DR Slochower, MK Gilson. Biophys J 114:2174, 2018, 10.1016/j.bpj.2018.02.008.

A Thermodynamic Limit on the Role of Self-Propulsion in Enhanced Enzyme Diffusion. Biophys J, 2019, in press (4/25/2019)

Translational drug design and molecular design projects

We are engaged in early-stage drug design projects in therapeutic areas that include pancreatic cancer and parasitic diseases., typically in collaboration with our research groups. We typically focus on therapeutic concepts with well-defined protein targets of known three-dimensional structure. We also are interested in more broader challenges in molecular design.

Selected publications

Discovering de novo peptide substrates for enzymes using machine learning. L Tallorin, JL Wang, WE Kim, S Sahu, NM Kosa, P Yang, M Thompson, MK Gilson, PI Frazier, MD Burkart, NC Gianneschi. Nature Comm 9:5253, 2018, 10.1038/s41467-018-07717-6.

Probing the orientation of inhibitor and epoxy-eicosatrienoic acid binding in the active site of soluble epoxide hydrolase. KS Lee, NM Henriksen, CJ Ng, J Yang, W Jia, C Morisseau, A Andaya, MK Gilson, BD Hammock. Arch Bioch Biophys 613:1, 2017, 10.1016/

Peptides displayed as high density brush polymers resist proteolysis and retain bioactivity. AP Blum, JK Kammeyer, J Yin, DT Crystal, AM Rush, MK Gilson, NC Gianneschi. JACS, 2014, 10.1021/ja5088216.

Supramolecular assembly promotes the electrocatalytic reduction of carbon dioxide by Re (I) bipyridine catalysts at a lower overpotential. CW Machan, SA Chabolla, J Yin, MK Gilson, FA Tezcan, CP Kubiak JACS 136:14598, 2014, 10.1021/ja5085282.


We thank our funders for their support of this work. Most of the work in our lab has been and is supported by the National Institute of General Medical Sciences, an institute of the National Institutes of Health. Our work has also been supported by other organizations, including the Air Force Office of Scientific Research and the National Science Foundation. Views expressed in this website and our publications are solely of the authors and do not necessarily represent the views of the funders.