Insights and Challenges in Correcting Force Field Based Solvation Free Energies Using a Neural Network Potential.

We present a comprehensive study investigating the potential gain in accuracy for calculating absolute solvation free energies (ASFE) using a neural network potential to describe the intramolecular energy of the solute. We calculated the ASFE for most compounds from the FreeSolv database using the Open Force Field (OpenFF) and compared them to earlier results obtained with the CHARMM General Force Field (CGenFF). By applying a nonequilibrium (NEQ) switching approach between the molecular mechanics (MM) description (either OpenFF or CGenFF) and the neural net potential (NNP)/MM level of theory (using ANI-2x as the NNP potential), we attempted to improve the accuracy of the calculated ASFEs.

Reweighting from Molecular Mechanics Force Fields to the ANI-2x Neural Network Potential.

To achieve chemical accuracy in free energy calculations, it is necessary to accurately describe the system's potential energy surface and efficiently sample configurations from its Boltzmann distribution. While neural network potentials (NNPs) have shown significantly higher accuracy than classical molecular mechanics (MM) force fields, they have a limited range of applicability and are considerably slower than MM potentials, often by orders of magnitude. To address this challenge, Rufa et al.

Calculations of Absolute Solvation Free Energies with Transformato─Application to the FreeSolv Database Using the CGenFF Force Field.

We recently introduced transformato, an open-source Python package for the automated setup of large-scale calculations of relative solvation and binding free energy differences. Here, we extend the capabilities of transformato to the calculation of absolute solvation free energy differences. After careful validation against the literature results and reference calculations with the PERT module of CHARMM, we used transformato to compute absolute solvation free energies for most molecules in the FreeSolv database (621 out of 642).

Factors Associated with Early Career Research Productivity after Ophthalmology Residency.

 Few studies have evaluated associations between ophthalmology trainee characteristics and performance with postgraduate research productivity.  This article evaluates factors associated with post-residency research productivity among U.S.

Protex-A Python utility for proton exchange in molecular dynamics simulations.

Protex is an open-source program that enables proton exchanges of solvent molecules during molecular dynamics simulations. While conventional molecular dynamics simulations do not allow for bond breaking or formation, protex offers an easy-to-use interface to augment these simulations and define multiple proton sites for (de-)protonation using a single topology approach with two different -states. Protex was successfully applied to a protic ionic liquid system, where each molecule is prone to (de-)protonation.

POLθ processes ssDNA gaps and promotes replication fork progression in BRCA1-deficient cells.

Polymerase theta (POLθ) is an error-prone DNA polymerase whose loss is synthetically lethal in cancer cells bearing breast cancer susceptibility proteins 1 and 2 (BRCA1/2) mutations. To investigate the basis of this genetic interaction, we utilized a small-molecule inhibitor targeting the POLθ polymerase domain. We found that POLθ processes single-stranded DNA (ssDNA) gaps that emerge in the absence of BRCA1, thus promoting unperturbed replication fork progression and survival of BRCA1 mutant cells.

Evaluation of commotio retinae in orbital fractures.

Purpose: This study aimed to evaluate the mechanisms of injury and types of orbital fractures and their relation to concurrent commotio retinae.

Methods: This retrospective study evaluated the records of patients with orbital fractures whose diagnoses had been confirmed by computer tomography between July 2017 and September 2019. Patient demographics, the circumstances of injury, ophthalmic examination results, and radiological findings were tabulated.

Relative binding free energy calculations with transformato: A molecular dynamics engine-independent tool.

We present the software package transformato for the setup of large-scale relative binding free energy calculations. Transformato is written in Python as an open source project (https://github.com/wiederm/transformato); in contrast to comparable tools, it is not closely tied to a particular molecular dynamics engine to carry out the underlying simulations.

Improving Small Molecule pK Prediction Using Transfer Learning With Graph Neural Networks.

Enumerating protonation states and calculating microstate pK values of small molecules is an important yet challenging task for lead optimization and molecular modeling. Commercial and non-commercial solutions have notable limitations such as restrictive and expensive licenses, high CPU/GPU hour requirements, or the need for expert knowledge to set up and use. We present a graph neural network model that is trained on 714,906 calculated microstate pK predictions from molecules obtained from the ChEMBL database.

Alchemical free energy simulations without speed limits. A generic framework to calculate free energy differences independent of the underlying molecular dynamics program.

We describe the theory of the so-called common-core/serial-atom-insertion (CC/SAI) approach to compute alchemical free energy differences and its practical implementation in a Python package called Transformato. CC/SAI is not tied to a specific biomolecular simulation program and does not rely on special purpose code for alchemical transformations. To calculate the alchemical free energy difference between several small molecules, the physical end-states are mutated into a suitable common core.

Synthesis and dopamine receptor binding of dihydrexidine and SKF 38393 catecholamine-based analogues.

Dopamine is an important neurotransmitter that regulates numerous essential functions, including cognition and voluntary movement. As such, it serves as an important scaffold for synthesis of novel analogues as part of drug development effort to obtain drugs for treatment of neurodegenerative diseases, such as Parkinson's disease. To that end, similarity search of the ZINC database based on two known dopamine-1 receptor (D1R) agonists, dihydrexidine (DHX) and SKF 38393, respectively, was used to predict novel chemical entities with potential binding to D1R.

Improved Lipophilicity and Aqueous Solubility Prediction with Composite Graph Neural Networks.

The accurate prediction of molecular properties, such as lipophilicity and aqueous solubility, are of great importance and pose challenges in several stages of the drug discovery pipeline. Machine learning methods, such as graph-based neural networks (GNNs), have shown exceptionally good performance in predicting these properties. In this work, we introduce a novel GNN architecture, called directed edge graph isomorphism network (D-GIN).

Fitting quantum machine learning potentials to experimental free energy data: predicting tautomer ratios in solution.

The computation of tautomer ratios of druglike molecules is enormously important in computer-aided drug discovery, as over a quarter of all approved drugs can populate multiple tautomeric species in solution. Unfortunately, accurate calculations of aqueous tautomer ratios-the degree to which these species must be penalized in order to correctly account for tautomers in modeling binding for computer-aided drug discovery-is surprisingly difficult. While quantum chemical approaches to computing aqueous tautomer ratios using continuum solvent models and rigid-rotor harmonic-oscillator thermochemistry are currently state of the art, these methods are still surprisingly inaccurate despite their enormous computational expense.

Impact of Anxiety Levels and Sleep Patterns on Perceived Pain During Intravitreal Bevacizumab Injections.

Background And Objective: To evaluate the impact of anxiety and sleep patterns on intravitreal injection pain.

Patients And Methods: This prospective, noninterventional study surveyed patients scheduled for intravitreal injection by two retinal surgeons. A standard intravitreal injection technique was used.

Central retinal artery occlusion associated with patent foramen ovale: a case report and literature review.

Patent foramen ovale might cause cryptogenic strokes, including retinal artery occlusion. Herein, we describe a previously healthy young man who presented with central retinal artery occlusion in the setting of patent foramen ovale and explore the need for transesophageal echocardiogram for its diagnosis. Cardiovascular workup and neuroimaging were unremarkable.

Dummy Atoms in Alchemical Free Energy Calculations.

In calculations of relative free energy differences, the number of atoms of the initial and final states is rarely the same. This necessitates the introduction of dummy atoms. These placeholders interact with the physical system only by bonded energy terms.

Social isolation and connection in adolescents with cancer and survivors of childhood cancer: A systematic review.

Introduction: Cancer may cause significant disruptions in normal adolescent development particularly in social domains. Both treatment and survivorship pose challenges to fostering social connections. To better understand these challenges, we conducted a systematic literature review of the experience of social isolation and connectedness in adolescents with cancer and adolescent survivors of childhood cancer.

Acute Vitreous and Intraretinal Hemorrhage with Multifocal Subretinal Fluid in Juvenile X-Linked Retinoschisis.

Purpose: To report a rare case of spontaneous vitreous and intraretinal hemorrhage in a patient with juvenile X-linked retinoschisis which was managed conservatively.

Methods: Single patient case report.

Introduction: Juvenile X-linked retinoschisis (JXLR) most often occurs as a result of a genetic defect in the retinoschisin (RS1) gene, causing a separation between the ganglion cell layer and the nerve fiber layer.

Bilateral serous retinal detachments associated with burkitt lymphoma.

Purpose: To report a case of bilateral serous retinal detachments in a patient found to have burkitt lymphoma.

Observations: A patient who presented with bilateral serous retinal detachments and "B" symptoms underwent extensive workup and was found to have burkitt lymphoma. Multiagent chemotherapy was initiated with resolution of the serous retinal detachments and visual recovery occurring in parallel to disease remission.

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships.

Computational Identification of Novel Kir6 Channel Inhibitors.

KATP channels consist of four Kir6.x pore-forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodilation of arterial smooth muscle cells.

Discovery of Potent Inhibitors for the Large Neutral Amino Acid Transporter 1 (LAT1) by Structure-Based Methods.

The large neutral amino acid transporter 1 (LAT1) is a promising anticancer target that is required for the cellular uptake of essential amino acids that serve as building blocks for cancer growth and proliferation. Here, we report a structure-based approach to identify chemically diverse and potent inhibitors of LAT1. First, a homology model of LAT1 that is based on the atomic structures of the prokaryotic homologs was constructed.

The Use of Dynamic Pharmacophore in Computer-Aided Hit Discovery: A Case Study.

In recent years pharmacophore modeling has become increasingly popular due to the development of software solutions and improvement in algorithms that allowed researchers to focus on interactions between protein and ligands instead of technical details of the software. At the same time, progress in computer hardware made molecular dynamics (MD) simulations on regular PC hardware possible. MD simulations are usually used, within the virtual screening process, to take into account the flexibility of the target and studying it in more realistic way.