Performance and Analysis of the Alchemical Transfer Method for Binding-Free-Energy Predictions of Diverse Ligands.

The Alchemical Transfer Method (ATM) is herein validated against the relative binding-free energies (RBFEs) of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and AToM-OpenMM software to compute the RBFEs of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations.

Developing end-point methods for absolute binding free energy calculation using the Boltzmann-quasiharmonic model.

Understanding the physical forces underlying receptor-ligand binding requires robust methods for analyzing the binding thermodynamics. In end-point binding free energy methods the binding free energy is naturally decomposable into physically intuitive contributions such as the solvation free energy and configurational entropy that can provide insights. Here we present a new end-point method called EE-BQH (Effective Energy-Boltzmann-Quasiharmonic) which combines the Boltzmann-Quasiharmonic model for configurational entropy with different solvation free energy methods, such as the continuum solvent PBSA model and the integral equation-based 3D-RISM, to estimate the absolute binding free energy.

Thermodynamic Decomposition of Solvation Free Energies with Particle Mesh Ewald and Long-Range Lennard-Jones Interactions in Grid Inhomogeneous Solvation Theory.

Grid Inhomogeneous Solvation Theory (GIST) maps out solvation thermodynamic properties on a fine meshed grid and provides a statistical mechanical formalism for thermodynamic end-state calculations. However, differences in how long-range nonbonded interactions are calculated in molecular dynamics engines and in the current implementation of GIST have prevented precise comparisons between free energies estimated using GIST and those from other free energy methods such as thermodynamic integration (TI). Here, we address this by presenting PME-GIST, a formalism by which particle mesh Ewald (PME)-based electrostatic energies and long-range Lennard-Jones (LJ) energies are decomposed and assigned to individual atoms and the corresponding voxels they occupy in a manner consistent with the GIST approach.

An online repository of solvation thermodynamic and structural maps of SARS-CoV-2 targets.

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets.

An online repository of solvation thermodynamic and structural maps of SARS-CoV-2 targets.

SARS-CoV-2 recently jumped species and rapidly spread via human-to-human transmission to cause a global outbreak of COVID-19. The lack of effective vaccine combined with the severity of the disease necessitates attempts to develop small molecule drugs to combat the virus. COVID19_GIST_HSA is a freely available online repository to provide solvation thermodynamic maps of COVID-19-related protein small molecule drug targets.

Hidden bias in the DUD-E dataset leads to misleading performance of deep learning in structure-based virtual screening.

Recently much effort has been invested in using convolutional neural network (CNN) models trained on 3D structural images of protein-ligand complexes to distinguish binding from non-binding ligands for virtual screening. However, the dearth of reliable protein-ligand x-ray structures and binding affinity data has required the use of constructed datasets for the training and evaluation of CNN molecular recognition models. Here, we outline various sources of bias in one such widely-used dataset, the Directory of Useful Decoys: Enhanced (DUD-E).

A Potent Antitumor Efficacy of Novel Recombinant Type I Interferon.

Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the and antitumorigenic activities of a novel recombinant IFN termed sIFN-I.

SMAC-armed vaccinia virus induces both apoptosis and necroptosis and synergizes the efficiency of vinblastine in HCC.

Hepatocellular carcinoma (HCC) has particularly high incidence rate in Asia and its resistance to the chemotherapeutic drugs and cell death make it intractable. Vaccinia virus (VV) is a potential vehicle and has been widely used in cancer therapy. SMAC/DIABLO is a critical factor in activating caspases and eliminating inhibition of IAPs when the programmed cell death is promoted.