A5037903278- Protein Structure and Dynamics
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Advanced Chemical Physics Studies
- Spectroscopy and Quantum Chemical Studies
- Enzyme Structure and Function
- Machine Learning in Materials Science
- Signaling Pathways in Disease
- RNA and protein synthesis mechanisms
- Advanced Thermodynamics and Statistical Mechanics
- Enzyme Catalysis and Immobilization
- Bioinformatics and Genomic Networks
- RNA Interference and Gene Delivery
- Gene Regulatory Network Analysis
- thermodynamics and calorimetric analyses
- Protein purification and stability
- Complex Network Analysis Techniques
- Protein Degradation and Inhibitors
- Bacterial Genetics and Biotechnology
Open Geospatial Consortium
2024-2025
Open Molecular Software Foundation
2024-2025
Io Therapeutics (United States)
2024
University of California, Irvine
2021-2024
Open Society Foundations
2024
Merck (Germany)
2020
Accurate ranking of compounds with regards to their binding affinity a protein using computational methods is great interest pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way estimate affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present results large-scale prospective application FEP+ method active drug discovery projects an setting at Merck KGaA,...
The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based estimates for 128 pharmaceutically relevant targets. We use novel rigorous method generate ensembles ligand its decoupled state. Not only do deliver affinity estimates,...
Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application prioritizing synthesis novel drug candidates. Relative (RBFE) have emerged as an industry-standard approach achieve highly accurate rank-order predictions related compounds; however, this requires that ligands share common scaffold mode, restricting methods' domain applicability. This is critical limitation since complex modifications ligands,...
Binding free energy calculations have become increasingly valuable to drive decision making in drug discovery projects. However, among other issues, inadequate sampling can reduce accuracy, limiting the value of technique. In this paper, we apply absolute binding ligands T4 lysozyme L99A and HSP90 using equilibrium nonequilibrium approaches. We highlight problems encountered these systems, such as slow side chain rearrangements changes water placement upon ligand binding. These same types...
Abstract In binding free energy calculations, simulations must sample all relevant conformations of the system in order to obtain unbiased results. For instance, different ligands can bind metastable states a protein, and if these protein conformational changes are not sampled relative contribution is accounted for thus calculated energies inaccurate. this work, we investigate impact beta‐sectretase 1 (BACE1) obtained from x‐ray crystallography on BACE1 inhibitors. We highlight how...
Relative binding free energy (RBFE) calculations have emerged as a powerful tool that supports ligand optimization in drug discovery. Despite many successes, the use of RBFEs can often be limited by automation problems, particular, setup such calculations. Atom mapping algorithms are an essential component setting up automatic large-scale hybrid-topology RBFE calculation campaigns. Traditional typically employ 2D subgraph isomorphism solver (SIS) order to estimate maximum common...
ABSTRACT Physics‐based methods such as protein‐ligand binding free energy calculations have been increasingly adopted in early‐stage drug discovery to prioritize promising compounds for synthesis. However, the accuracy of these is highly dependent on details calculation and choices made while preparing ligands protein ahead running calculations. During ligand preparation, researchers typically assign partial atomic charges each atom using a specific conformation charge assignment, often...
Recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies remains a challenging endeavour, mostly limited to small model cases. We demonstrate accurate estimates for 128 pharmaceutically relevant ligands across 7 proteins using highly parallelizable non-equilibrium method. These also provide detailed physical insight into structural determinants binding, identifying subtle...
The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as potential therapeutic approach for treating multiple sclerosis. Herein, we describe discovery and optimization brain-penetrant, orally bioavailable inhibitors EBP. A structure-based drug design from literature compound 1 led to hydantoin-based scaffold, provided balanced physicochemical properties potency an improved...
Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application prioritizing synthesis novel drug candidates. Relative (RBFE) have emerged as an industry standard approach achieve highly accurate rank-order predictions related compounds; however, this requires that ligands share common scaffold mode, restricting methods' domain applicability. This is critical limitation, since complex modifications ligands,...
Water often plays a key role in mediating protein-ligand interactions. Understanding contributions from active-site water molecules to binding thermodynamics of ligand is important predicting free energies for optimization. In this work, we tested non-equilibrium switching method absolute energy calculations on sites 13 systems. We discuss the lessons learned about identified issues that affected our and ways address them. This work fits with larger focus how do accurate when rearrangements...
Alchemical free energy campaigns can be planned using graph theory by building networks that contain nodes representing molecules are connected possible transformations as edges. We introduce Konnektor, an open-source Python package, for systematically planning, modifying, and analyzing calculation networks. Konnektor is designed to aid in the drug discovery process enabling users easily setup complex manipulation methods. The package contains functions network operations including...
Physics-based methods such as protein-ligand binding free energy calculations have been increasingly adopted in early-stage drug discovery to prioritize promising compounds for synthesis. However, the accuracy of these is highly dependent on details calculation and choices made while preparing ligands protein ahead running calculations. During ligand preparation, researchers typically assign partial atomic charges each atom using a specific conformation charge assignment, often input...
Water often plays a key role in mediating protein-ligand interactions. Understanding contributions from active-site water molecules to binding thermodynamics of ligand is important predicting free energies for optimization. In this work, we tested nonequilibrium switching method absolute energy calculations on sites 13 systems. We discuss the lessons learned about identified issues that affected our and ways address them. This work fits with larger focus how do accurate when rearrangements...
The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based estimates for 128 pharmaceutically relevant targets. We use novel rigorous method generate ensembles ligand its decoupled state. Not only do deliver affinity estimates,...
Binding free energy calculations predict the potency of compounds to protein binding sites in a physically rigorous manner and see broad application prioritizing synthesis novel drug candidates. Relative (RBFE) have emerged as an industry standard approach achieve highly accurate rank-order predictions related compounds; however, this requires that ligands share common scaffold mode, restricting methods' domain applicability. This is critical limitation, since complex modifications ligands,...
Water often plays a key role in mediating protein-ligand interactions. Understanding contributions from active-site water molecules to binding thermodynamics of ligand is important predicting free energies for optimization. In this work, we tested nonequilibrium switching method absolute energy calculations on sites. We studied five protein targets with different ligands which the selected buried sites had been by previous work using simulation technique. Our calculated agree well literature...
Recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies remains a challenging endeavour, mostly limited to small model cases. We demonstrate accurate estimates for 128 pharmaceutically relevant ligands across 7 proteins using highly parallelizable non-equilibrium method. These also provide detailed physical insight into structural determinants binding, identifying subtle...
The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods drug discovery. Accurately assessing absolute energies, although highly desired, remains a challenging endeavour, mostly limited to small model cases. Here, we demonstrate accurate first principles based estimates for 128 pharmaceutically relevant targets. We use novel rigorous method generate ensembles ligand its decoupled state. Not only do deliver affinity estimates,...