Alexander D. MacKerell
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View article: Arrhythmia Risk Predictions from Molecular Simulations of Cardiac Ion Channel-Drug Interactions
Arrhythmia Risk Predictions from Molecular Simulations of Cardiac Ion Channel-Drug Interactions Open
Unintended block of cardiac ion channels, particularly hERG (KV11.1), remains a key concern in drug development as disruption of ion channel function can lead to deadly arrhythmia. To assess proarrhythmic risk, we investigated h…
View article: Prediction of TdP Arrhythmia Risk Through Molecular Simulations of Conformation-specific Drug Interactions with the hERG K<sup>+</sup>, Na<sub>V</sub>1.5, and Ca<sub>V</sub>1.2 Channels
Prediction of TdP Arrhythmia Risk Through Molecular Simulations of Conformation-specific Drug Interactions with the hERG K<sup>+</sup>, Na<sub>V</sub>1.5, and Ca<sub>V</sub>1.2 Channels Open
Unintended block of cardiac ion channels, particularly hERG (K V 11.1), remains a key concern in drug development as disruption of ion channel function can lead to deadly arrhythmia. To assess proarrhythmic risk, we investigated how drugs …
View article: Bile Acids Are Potential Negative Allosteric Modulators of M1 Muscarinic Receptors
Bile Acids Are Potential Negative Allosteric Modulators of M1 Muscarinic Receptors Open
The proposed physiological roles of bile acids have expanded beyond the digestion of fats to encompass cell signaling via the activation of a variety of nuclear and plasma membrane receptors in multiple organ systems. The current in silico…
View article: The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication
The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication Open
There is a need for the development of broad-spectrum antiviral compounds that can act as first-line therapeutic countermeasures to emerging viral infections. Host-directed approaches present a promising avenue of development and carry the…
View article: GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp
GaSal-2: A Water-Soluble Antipseudomonal Agent Targeting the Extracellular Hemophore HasAp Open
Multidrug-resistant Pseudomonas aeruginosa is a critical pathogen that demands new antibiotics. During P. aeruginosa infection, the extracellular hemophore hasAp and its outer membrane receptor hasR are the most…
View article: Harnessing computational technologies to facilitate antibody–drug conjugate development
Harnessing computational technologies to facilitate antibody–drug conjugate development Open
View article: High Throughput Ligand Dissociation Kinetics Predictions using Site-Identification by Ligand Competitive Saturation
High Throughput Ligand Dissociation Kinetics Predictions using Site-Identification by Ligand Competitive Saturation Open
The dissociation or off rate, koff, of a drug molecule has been shown to be more relevant to efficacy than affinity for selected systems motivating the development of predictive computational methodologies. These are largely based on enhan…
View article: The need to implement FAIR principles in biomolecular simulations
The need to implement FAIR principles in biomolecular simulations Open
International audience
View article: Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies
Potent and Selective Human Constitutive Androstane Receptor Activator DL5055 Facilitates Cyclophosphamide-Based Chemotherapies Open
Enhancement of the metabolic conversion of cyclophosphamide (CPA) increases its therapeutic effects. Activation of the human constitutive androstane receptor (hCAR) induces CYP2B6, a key enzyme responsible for CPA bioactivation. Based on o…
View article: Mapping the Distribution and Affinities of Ligand Interaction Sites on Human Serum Albumin
Mapping the Distribution and Affinities of Ligand Interaction Sites on Human Serum Albumin Open
Ligands in many instances interact with a protein at multiple sites with a range of affinities. In the present study, ligand-protein interaction sites on Human Serum Albumin (HSA) are mapped using the site-identification by ligand competit…
View article: Increasing the Accuracy and Robustness of the CHARMM General Force Field with an Expanded Training Set
Increasing the Accuracy and Robustness of the CHARMM General Force Field with an Expanded Training Set Open
Small molecule empirical force fields (FFs), including the CHARMM General Force Field (CGenFF), are designed to have wide coverage of organic molecules and to rapidly assign parameters to molecules not explicitly included in the FF. Assign…
View article: High Throughput Ligand Dissociation Kinetics Predictions using Site-Identification by Ligand Competitive Saturation
High Throughput Ligand Dissociation Kinetics Predictions using Site-Identification by Ligand Competitive Saturation Open
The dissociation or off rate, koff, of a drug molecule has been shown to be more relevant to efficacy than affinity for selected systems motivating the development of predictive computational methodologies. These are largely based on enhan…
View article: Non-Covalent Molecular Interaction Rules to Define Internal Dimer Coordinates for Quantum Mechanical Potential Energy Scans
Non-Covalent Molecular Interaction Rules to Define Internal Dimer Coordinates for Quantum Mechanical Potential Energy Scans Open
Non-covalent interactions (NCI) dominate the properties of condensed phase systems. Towards a detailed understanding of NCI quantum mechanical (QM) methods allow for accurate estimates of interaction energies and geometries, allowing for t…
View article: Increasing the Accuracy and Robustness of the CHARMM General Force Field with an Expanded Training Set
Increasing the Accuracy and Robustness of the CHARMM General Force Field with an Expanded Training Set Open
Small molecule empirical force fields (FFs), including the CHARMM General Force Field (CGenFF), are designed to have wide coverage of organic molecules and to rapidly assign parameters to molecules not explicitly included in the FF. Assign…
View article: Mapping the Distribution and Affinities of Ligand Interaction Sites on Human Serum Albumin
Mapping the Distribution and Affinities of Ligand Interaction Sites on Human Serum Albumin Open
Ligands in many instances interact with a protein at multiple sites with a range of affinities. In the present study, ligand-protein interaction sites on Human Serum Albumin (HSA) are mapped using the site-identification by ligand competit…
View article: The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication
The mammalian SKI complex is a broad-spectrum antiviral drug target that upregulates cellular cholesterol to inhibit viral replication Open
There is a need for the development of broad-spectrum antiviral compounds that can act as first line therapeutic countermeasures to emerging viral infections. Host-directed approaches present a promising avenue of development and carry the…
View article: Revised 4-Point Water Model for the Classical Drude Oscillator Polarizable Force Field: SWM4-HLJ
Revised 4-Point Water Model for the Classical Drude Oscillator Polarizable Force Field: SWM4-HLJ Open
In this work the 4-point polarizable SWM4 Drude water model is reparametrized. Multiple models were developed using different strategies toward reproduction of specific target data. Results indicate that no individual model can reproduce a…
View article: Refinement of the Drude Polarizable Force Field for Hexose Monosaccharides: Capturing Ring Conformational Dynamics with Enhanced Accuracy
Refinement of the Drude Polarizable Force Field for Hexose Monosaccharides: Capturing Ring Conformational Dynamics with Enhanced Accuracy Open
We present a revised version of the Drude polarizable carbohydrate force field (FF), focusing on refining the ring and exocyclic torsional parameters for hexopyranose monosaccharides. This refinement addresses the previously observed discr…
View article: Detection of Putative Ligand Dissociation Pathways in Proteins using Site-Identification by Ligand Competitive Saturation
Detection of Putative Ligand Dissociation Pathways in Proteins using Site-Identification by Ligand Competitive Saturation Open
Drug efficacy often correlates better with dissociation kinetics than binding affinity alone. To study binding kinetics computationally, it is necessary to identify all possible ligand dissociation pathways. The site identification by liga…
View article: First-in-Class Mitogen-Activated Protein Kinase p38α: MAPK-Activated Protein Kinase-2 (MK2) Dual Signal Modulator with Anti-inflammatory and Endothelial-stabilizing Properties.
First-in-Class Mitogen-Activated Protein Kinase p38α: MAPK-Activated Protein Kinase-2 (MK2) Dual Signal Modulator with Anti-inflammatory and Endothelial-stabilizing Properties. Open
We previously identified a small molecule, UM101, predicted to bind to the substrate-binding groove of p38aMitogen-activated Protein Kinase (MAPK) near the binding site of its proinflammatory substrate, MAPK-activated protein kinase (MK2).…
View article: CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed
CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed Open
Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of…
View article: Combined Physics- and Machine-Learning-Based Method to Identify Druggable Binding Sites Using SILCS-Hotspots
Combined Physics- and Machine-Learning-Based Method to Identify Druggable Binding Sites Using SILCS-Hotspots Open
Identifying druggable binding sites on proteins is an important and challenging problem, particularly for cryptic, allosteric binding sites that may not be obvious from X-ray, cryo-EM, or predicted structures. The Site-Identification by Li…
View article: Exploring Druggable Binding Sites on the Class A GPCRs Using the Residue Interaction Network and Site Identification by Ligand Competitive Saturation
Exploring Druggable Binding Sites on the Class A GPCRs Using the Residue Interaction Network and Site Identification by Ligand Competitive Saturation Open
G protein-coupled receptors (GPCRs) play a central role in cellular signaling and are linked to many diseases. Accordingly, computational methods to explore potential allosteric sites for this class of proteins to facilitate the identifica…
View article: Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis
Investigating the Interaction between Excipients and Monoclonal Antibodies PGT121 and N49P9.6-FR-LS: A Comprehensive Analysis Open
N49P9.6-FR-LS and PGT121 are promising antibodies with significant therapeutic potential against HIV infection, but they are prone to precipitation at high concentrations. This study evaluates the influence of six excipients—L-arginine, L-…
View article: Combined physics- and machine-learning-based method to identify druggable binding sites using SILCS-Hotspots
Combined physics- and machine-learning-based method to identify druggable binding sites using SILCS-Hotspots Open
Identifying druggable binding sites on proteins is an important and challenging problem, particularly for cryptic, allosteric binding sites that may not be obvious from X-ray, cryo-EM, or predicted structures. The Site-Identification by Li…
View article: The need to implement FAIR principles in biomolecular simulations
The need to implement FAIR principles in biomolecular simulations Open
This letter illustrates the opinion of the molecular dynamics (MD) community on the need to adopt a new FAIR paradigm for the use of molecular simulations. It highlights the necessity of a collaborative effort to create, establish, and sus…
View article: Enhancing SILCS-MC via GPU Acceleration and Ligand Conformational Optimization with Genetic and Parallel Tempering Algorithms
Enhancing SILCS-MC via GPU Acceleration and Ligand Conformational Optimization with Genetic and Parallel Tempering Algorithms Open
In the domain of computer-aided drug design, achieving precise and accurate estimates of ligand-protein binding is paramount in the context of screening extensive drug libraries and performing ligand optimization. A fundamental aspect of t…
View article: Combined physics- and machine-learning-based method to identify druggable binding sites using SILCS-Hotspots
Combined physics- and machine-learning-based method to identify druggable binding sites using SILCS-Hotspots Open
Identifying druggable binding sites on proteins is an important and challenging problem, particularly for cryptic, allosteric binding sites that may not be obvious from X-ray, cryo-EM, or predicted structures. The Site-Identification by Li…
View article: Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation
Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation Open
The chemokine receptor CXCR4 is a critical target for the treatment of several cancer types and HIV-1 infections. While orthosteric and allosteric modulators have been developed targeting its extracellular or transmembrane regions, the int…
View article: Balancing Group I Monatomic Ion–Polar Compound Interactions for Condensed Phase Simulation in the Polarizable Drude Force Field
Balancing Group I Monatomic Ion–Polar Compound Interactions for Condensed Phase Simulation in the Polarizable Drude Force Field Open
Molecular dynamics (MD) simulations are a commonly used method for investigating molecular behavior at the atomic level. Achieving reliable MD simulation results necessitates the use of an accurate force field. In the present work, we pres…