CovCysPredictor: Predicting Selective Covalently Modifiable Cysteines Using Protein Structure and Interpretable Machine Learning.

Targeted covalent inhibition is a powerful therapeutic modality in the drug discoverer's toolbox. Recent advances in covalent drug discovery, in particular, targeting cysteines, have led to significant breakthroughs for traditionally challenging targets such as mutant KRAS, which is implicated in diverse human cancers. However, identifying cysteines for targeted covalent inhibition is a difficult task, as experimental and in silico tools have shown limited accuracy.

Discovery of Truncated Cyclic Peptides Targeting an Induced-Fit Pocket on PCSK9.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDL-R) degradation. We previously identified and optimized 13-mer cyclic peptides that bind to a novel, induced-fit pocket adjacent to the binding interface of PCSK9 and LDL-R and effectively disrupted the PCSK9/LDL-R protein-protein interaction (PPI) both in vitro and in vivo. However this series of large cyclic peptides required charged groups for function and lacked oral bioavailability in rodents.

Leveraging Advanced In Silico Techniques in Early Drug Discovery: A Study of Potent Small-Molecule YAP-TEAD PPI Disruptors.

Disruption of the YAP-TEAD protein-protein interaction is an attractive therapeutic strategy in oncology to suppress tumor progression and cancer metastasis. YAP binds to TEAD at a large flat binding interface (∼3500 Å) devoid of a well-defined druggable pocket, so it has been difficult to design low-molecular-weight compounds to abrogate this protein-protein interaction directly. Recently, work by Furet and coworkers ( , DOI: 10.

Benchmarking Tools for Cysteine p Prediction.

Accurate estimation of the p's of cysteine residues in proteins could inform targeted approaches in hit discovery. The p of a targetable cysteine residue in a disease-related protein is an important physiochemical parameter in covalent drug discovery, as it influences the fraction of nucleophilic thiolate amenable to chemical protein modification. Traditional structure-based tools are limited in their predictive accuracy of cysteine p's relative to other titratable residues.

Identification of a PCSK9-LDLR disruptor peptide with in vivo function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma low-density lipoprotein cholesterol (LDL-C) levels by promoting hepatic LDL receptor (LDLR) degradation. Therapeutic antibodies that disrupt PCSK9-LDLR binding reduce LDL-C concentrations and cardiovascular disease risk. The epidermal growth factor precursor homology domain A (EGF-A) of the LDLR serves as a primary contact with PCSK9 via a flat interface, presenting a challenge for identifying small molecule PCSK9-LDLR disruptors.

Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure.

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel but independent tracks. Less precedent combines their respective attributes, thereby limiting the potential to identify permeable peptide ligands for key targets. Herein, we present novel 6-, 7-, and 8-mer cyclic peptides (MW 774-1076 g·mol) with passive permeability and oral exposure that feature the amino acids and thioether ring-closing common to large array formats, including DNA- and RNA-templated synthesis.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.

The main protease (M) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M, a cysteine protease, have been determined, facilitating structure-based drug design. M plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.

The main protease (M ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M , a cysteine protease, have been determined, facilitating structure-based drug design. M plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins.

The mechanism of the translocation step in DNA replication by DNA polymerase I: a computer simulation analysis.

High-fidelity DNA polymerases copy DNA rapidly and accurately by adding correct deoxynucleotide triphosphates to a growing primer strand of DNA. Following nucleotide incorporation, a series of conformational changes translocate the DNA substrate by one base pair step, readying the polymerase for the next round of incorporation. Molecular dynamics simulations indicate that the translocation consists globally of a polymerase fingers-opening transition, followed by the DNA displacement and the insertion of the template base into the preinsertion site.

Probing polar solvation dynamics in proteins: a molecular dynamics simulation analysis.

Measurements of time-resolved Stokes shifts on picosecond to nanosecond time scales have been used to probe the polar solvation dynamics of biological systems. Since it is difficult to decompose the measurements into protein and solvent contributions, computer simulations are useful to aid in understanding the details of the molecular behavior. Here we report the analysis of simulations of the electrostatic interactions of the rest of the protein and the solvent with 11 residues of the immunoglobulin binding domain B1 of protein G.