A5082183119- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Machine Learning in Materials Science
- Chronic Myeloid Leukemia Treatments
- Chronic Lymphocytic Leukemia Research
- Enzyme Structure and Function
- Melanoma and MAPK Pathways
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Metabolomics and Mass Spectrometry Studies
- Crystallography and molecular interactions
- T-cell and B-cell Immunology
- Microtubule and mitosis dynamics
- Lymphoma Diagnosis and Treatment
- Chemistry and Chemical Engineering
- DNA Repair Mechanisms
- Cytokine Signaling Pathways and Interactions
- Mass Spectrometry Techniques and Applications
- RNA and protein synthesis mechanisms
- Receptor Mechanisms and Signaling
- Heat shock proteins research
- Cancer-related Molecular Pathways
Schrodinger (United States)
2018-2025
University of Michigan
2015-2021
We present a reliable and accurate solution to the induced fit docking problem for protein–ligand binding by combining ligand-based pharmacophore docking, rigid receptor protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective prospective testing succeeded determine modes root-mean-square deviation within 2.5 Å over 90% of cross-docking cases. further demonstrate these predicted ligand–receptor structures were...
Mixed-solvent molecular dynamics (MixMD) is a hotspot-mapping technique that relies on simulations of proteins in binary solvent mixtures. Previous work MixMD has established the technique's effectiveness capturing binding sites small organic compounds. In this work, we show can identify both competitive and allosteric proteins. The approach embraces full protein flexibility allows competition between probes water. Sites preferentially mapped by probe molecules are more likely to be...
TYK2 is a key mediator of IL12, IL23, and type I interferon signaling, these cytokines have been implicated in the pathogenesis multiple inflammatory autoimmune diseases such as psoriasis, rheumatoid arthritis, lupus, bowel diseases. Supported by compelling data from human genome-wide association studies clinical results, inhibition through small molecules an attractive therapeutic strategy to treat Herein, we report discovery series highly selective pseudokinase (Janus homology 2, JH2)...
ABSTRACT Mixed‐solvent molecular dynamics (MixMD) simulations use full protein flexibility and competition between water small organic probes to achieve accurate hot‐spot mapping on surfaces. In this study, we improved MixMD using human immunodeficiency virus type‐1 protease (HIVp) as the test case. We used three probe–water solutions (acetonitrile–water, isopropanol–water, pyrimidine–water), first at 50% w/w concentration later 5% v/v. Paradoxically, better was achieved by fewer probes;...
The hit identification process usually involves the profiling of millions to more recently billions compounds either via traditional experimental high-throughput screens (HTS) or computational virtual (vHTS). We have previously demonstrated that, by coupling reaction-based enumeration, active learning, and free energy calculations, a similarly large-scale exploration chemical space can be extended hit-to-lead process. In this work, we augment that approach large scale enumeration cloud-based...
Drug resistance is a critical challenge in treating diseases like cancer and infectious disease. This study presents novel computational workflow for predicting on-target mutations to small molecule inhibitors (SMIs). The approach integrates genetic models with alchemical free energy perturbation (FEP+) calculations identify likely mutations. Specifically, model, RECODE, leverages cancer-specific mutation patterns prioritize probable amino acid changes. Physics-based assess the impact of...
The ability to target protein–protein interactions (PPIs) with small molecule inhibitors offers great promise in expanding the druggable space and addressing a broad range of untreated diseases. However, due their nature function interacting protein partners, PPI interfaces tend extend over large surfaces without typical pockets enzymes receptors. These features present unique challenges for inhibitor design. As such, determining whether particular interest could be pursued discovery...
We report on the development and validation of OPLS5 force field. further extends accuracy our previous model (OPLS4) with addition explicit polarization to improve for molecular ions cation-pi interactions. also includes advances functional form metals achieving significant improvements across benchmarks assessing structure energetics metal-organic complexes. Together these lead improved protein-ligand binding benchmarks.
Inhibition of Bruton tyrosine kinase (BTK) is a breakthrough therapy for certain B cell lymphomas and chronic lymphatic leukemia. Covalent BTK inhibitors (e.g., ibrutinib) bind to cysteine C481, mutations this residue confer clinical resistance. This has led the development noncovalent that do not require binding C481. These new compounds are now entering trials. In systematic mutagenesis screen, we identify residues critical activity inhibitors. include gatekeeper (T474) in domain....
In our recent efforts to map protein surfaces using mixed-solvent molecular dynamics (MixMD) (Ghanakota, P.; Carlson, H. A. Moving Beyond Active-Site Detection: MixMD Applied Allosteric Systems. J. Phys. Chem. B 2016, 120, 8685–8695), we were able successfully capture active sites and allosteric within the top-four most occupied hotspots. this study, describe approach for estimating thermodynamic profile of binding identified by MixMD. First, establish a framework calculating free energies...
Understanding the mechanistic basis of prodrug delivery and activation is critical for establishing species-specific sensitivities necessary evaluating preclinical animal models potential drug-drug interactions. Despite significant adoption methodologies enhanced pharmacokinetics, functional annotation activating enzymes laborious often unaddressed. Activity-based protein profiling (ABPP) describes an emerging chemoproteomic approach to assay active site occupancy within a mechanistically...
We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore (Phase), rigid receptor (Glide), protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. provide an in-depth description of our novel methodology results 41 targets consisting 415 cross-docking cases divided amongst training test set. For both test-set, we compute modes ligand-heavy atom RMSD within 2.5 Å or...
The hit identification process usually involves the profiling of millions to more recently billions compounds either via traditional experimental high throughput screens (HTS) or computational virtual (vHTS). We have previously demonstrated that by coupling reaction-based enumeration, active learning and free energy calculations, a similarly large-scale exploration chemical space can be extended hit-to-lead process. In this work, we augment approach large scale enumeration cloud-based FEP...
The hit identification process usually involves the profiling of millions to more recently billions compounds either via traditional experimental high throughput screens (HTS) or computational virtual (vHTS). We have previously demonstrated that by coupling reaction-based enumeration, active learning and free energy calculations, a similarly large-scale exploration chemical space can be extended hit-to-lead process. In this work, we augment approach large scale enumeration cloud-based FEP...
Drug resistance is a critical challenge in treating diseases like cancer and infectious disease. This study presents novel computational workflow for predicting on-target mutations to small molecule inhibitors (SMIs). The approach integrates genetic models with alchemical free energy perturbation (FEP+) calculations identify likely mutations. Specifically, model, RECODE, leverages cancer-specific mutation patterns prioritize probable amino acid changes. Physics-based assess the impact of...
We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore (Phase), rigid receptor (Glide), protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. provide an in-depth description of our novel methodology results 41 targets consisting 415 cross-docking cases divided amongst training test set. For both test-set, we compute modes ligand-heavy atom RMSD within 2.5 Å or...
We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore (Phase), rigid receptor (Glide), protein structure prediction (Prime) with explicit solvent molecular dynamics simulations. provide an in-depth description of our novel methodology results 41 targets consisting 415 cross-docking cases divided amongst training test set. For both test-set, we compute modes ligand-heavy atom RMSD within 2.5 Å or...
Abstract Introduction: CDC7 is a serine/threonine protein kinase that phosphorylates the MCM2-7 helicase complex, required step in DNA replication initiation. has emerged as an attractive target for cancer treatment because of high expression number tumors (e.g. ovarian, lung, and oral) which thought to be linked their proliferative capacity ability bypass damage responses. Consistent with this, disruption activity cells results delayed replication, mitotic abnormalities cell death whereas...