Recent Drug Discovery Publications

GPCRs

Using AlphaFold and experimental structures for the prediction of the structure and binding affinities of GPCR complexes via induced fit docking and free energy perturbation. Coskun D, et al. J Chem Theory Comput. 2023, 20, 477-489.

Is the functional response of a receptor determined by the thermodynamics of ligand binding? Vögele M, et al. J Chem Theory Comput. 2023, 19, 22, 8414-8422.

Accurate prediction of GPCR ligand binding affinity with free energy perturbation. Deflorian F, et al. J Chem Inf Model. 2020, 60, 5563-5579.

Discovery of biased and potent apelin receptor agonists using structure-based drug design. ACS Fall 2023 – Poster. Presented by Xichen Lin and Hui Lei. Structure Therapeutics.

Predicting binding affinities for GPCR ligands using free-energy perturbation. ACS Omega. 2016, 1, 2, 293–304.

Kinases

In silico enabled discovery of KAI-11101, a preclinical DLK inhibitor for the treatment of neurodegenerative disease and neuronal injury. Lagiakos R, et al. J Med Chem. 2025, 68, 3, 2720-2741.

Discovery of a novel mutant-selective epidermal growth factor receptor inhibitor using an in silico enabled drug discovery platform. Igawa H et al. J Med Chem. 2024, 67, 24, 21811-21840.

Harnessing free energy calculations to achieve kinome-wide selectivity in drug discovery campaigns: Wee1 case study. Knight J, et al. ChemRxiv. Posted August 2024.

Discovery of a potent and selective tyrosine kinase 2 inhibitor: TAK-279. Silvana L, et al. J Med Chem. 2023, 66, 15, 10473-10496.

Ion Channels

Basic residues at position 11 of α-conotoxin LvIA influence subtype selectivity between α3β2 and α3β4 nicotinic receptors via an electrostatic mechanism. Haufe Y, et al. ACS Chem Neurosci. 2023, 14, 24, 4311-4322.

Potency-enhancing mutations of gating modifier toxins for the voltage-gated sodium channel NaV1.7 can be predicted using accurate free-energy calculations. Katz D, et al. Toxins (Basel). 2021, 13, 3, 193.

Non-Kinase Enzymes

Structure-based discovery and development of highly potent dihydroorotate dehydrogenase inhibitors for malaria chemoprevention. Nie Z, et al. J Med Chem.  2025, 68, 1, 590-637.

Discovery of a novel class of D-amino acid oxidase inhibitors using the Schrödinger computational platform. Tang H, et al. J Med Chem. 2022, 65, 9, 6775-6802. 

[1,2,4]Triazolo[1,5-a]pyrimidine phosphodiesterase 2A inhibitors: Structure and free-energy perturbation-guided exploration. Tresadern G, et al. J Med Chem. 2020, 63, 21, 12887-12910

Proteases

Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity. Carney DW, et al. Bioorg Med Chem. 2024, 103, 117577.

Design and optimization of novel competitive, non-peptidic, SARS-CoV-2 Mpro inhibitors. Jacobs L, et al. ACS Med Chem Lett. 2023, 14, 10, 1434-1440.

Discovery of potent, selective, and orally bioavailable inhibitors of USP7 with in vivo anti-tumor activity. Leger PR, et al. J Med Chem. 2020, 63, 10, 5398-5420.

Peptides

Basic residues at position 11 of α-conotoxin LvIA influence subtype selectivity between α3β2 and α3β4 nicotinic receptors via an electrostatic mechanism. Haufe Y, et al. ACS Chem Neurosci. 2023, 14, 24, 4311-4322.

Computational design and biological evaluation of analogs of lupin peptide P5 endowed with dual PCSK9/HMG-CoAR inhibiting activity. Lammi C, et al. Pharmaceutics. 2022, 14, 3, 665.

Potency- and selectivity-enhancing mutations of conotoxins for nicotinic acetylcholine receptors can be predicted using accurate free-energy calculations. Katz D, et al. Mar Drugs. 2021, 19, 7, 367.

RNA and DNA

Accurate physics-based prediction of binding affinities of RNA- and DNA-targeting ligands. Abramyan AM, et al. J Chem Inf Model. 2025, 65, 3, 1392–1403.

Protein-Protein Interactions

Robust prediction of relative binding energies for protein–protein complex mutations using free energy perturbation calculations. Sampson JM, et al. J Mol Biol. 2024, 436, 16, 168640.

Free energy perturbation calculation of relative binding free energy between broadly neutralizing antibodies and the gp120 glycoprotein of HIV-1. Clark AJ, et al. J Mol Biol. 2017, 429, 7, 930-947.

Relative binding affinity prediction of charge-changing sequence mutations with FEP in protein-protein interfaces. Clark AJ, et al. J Mol Biol. 2019, 431, 7, 1481-1493.

Induced Proximity

Quantifying cooperativity through binding free energies in molecular glue degraders. J. Chem. Theory Comput. 2025, 21, 11, 5712–5723

Affinity and cooperativity modulate ternary complex formation to drive targeted protein degradation. Wurz R, et al. Nat Commun. 2023, 14, 4177.

On ternary complex stability in protein degradation: In silico molecular glue binding affinity calculations. Weiss DR, et al. J Chem Inf Model. 2023, 63, 8, 2382-2392.

Using Cryo-EM Structures or AI-Predicted Structures

Enabling structure-based drug discovery utilizing predicted models. Miller EB, et al. Cell. 2024, 187, 3, 521-525.

Structures of synaptic vesicle protein 2A and 2B bound to anticonvulsants. Mittal A, et al. Nat Struct Mol Biol. 2024, 31, 1964-1974.

Benchmarking refined and unrefined AlphaFold2 structures for hit discovery. Zhang Y, et al. J Chem Inf Model. 2023, 63, 6, 1656-1667.

Reliable and accurate solution to the induced fit docking problem for protein-ligand binding. Miller EB, et al. J Chem Theory Comput. 2021, 17, 4, 2630-2639.

An allosteric mechanism for potent inhibition of human ATP-citrate lyase. Wei J, et al. Nature. 2019, 568, 566-570.

Applications of AI/ML and De Novo Design

AutoDesigner – Core Design, a de novo design algorithm for chemical scaffolds: Application to the design and synthesis of novel selective Wee1 inhibitors. Bos PH, et al. J Chem Inf Model. 2024, 64, 19, 7513-7524.

FEP augmentation as a means to solve data paucity problems for machine learning in chemical biology. Burger PB, et al. J Chem Inf Model. 2024, 64, 9, 3812-3825.

AutoDesigner, a de novo design algorithm for rapidly exploring large chemical space for lead optimization: Application to the design and synthesis of D-amino acid oxidase inhibitors. Bos PH, et al. J Chem Inf Model. 2022, 62, 8, 1905-1915.

Efficient exploration of chemical space with docking and deep learning. Yang Y, et al. J Chem Theory Comput. 2021, 17, 11, 7106-7119.