Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure-Activity Relationships.

Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity.

Applications of Model-Based Target Pharmacology Assessment in Defining Drug Design and DMPK Strategies: GSK Experiences.

Many critical decisions faced in early discovery require a thorough understanding of the dynamic behavior of pharmacological pathways following target engagement. From fundamental decisions on the optimal target to pursue and the ultimate drug product profile (combination of modality, potency, and compound properties) expected to elicit the desired clinical outcome to tactical program decisions such as what chemical series to pursue, what chemical properties require optimization, and what compounds to synthesize and progress, all demand detailed consideration of pharmacodynamics. Model-based target pharmacology assessment (mTPA) is a computational approach centered around large-scale virtual exploration of pharmacokinetic and pharmacodynamic models built early in discovery to guide these decisions.

Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase.

All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside and non-nucleoside inhibitors (NNI) that target the DNA-bound state of herpesvirus polymerase and block replication. Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OXR) have shown promise as novel therapeutics that directly target the pathophysiology of the disease.

Women Make COMP: Mentoring the Next Generation of Women in Computational Chemistry.

The Women Make COMP symposium (258th American Chemical Society Meeting) aims at inspiring, motivating, and supporting young women in computational and theoretical chemistry. As a role model of the event, Ada Lovelace (1815-1852) was an English mathematician and writer, known for having founded computing science.

Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics.

In this study, we demonstrate the extensive scalability of the biasing potential replica exchange multisite λ dynamics (BP-REX MSλD) free energy method by calculating binding affinities for 512 inhibitors to HIV Reverse Transcriptase (HIV-RT). This is the largest exploration of chemical space using free energy methods known to date, requires only a few simulations, and identifies 55 new inhibitor designs against HIV-RT predicted to be at least as potent as a tight binding reference compound (i.e.

The Transition from Academia: Overcoming the Barrier to a Career in the Drug Discovery Industry.

This perspective describes the transition from academic training (specifically graduate school and a postdoctoral fellowship) to a career in the pharmaceutical industry as a computational chemist. My personal journey from childhood to senior scientist is described, along with suggestions and insights into a career in the pharmaceutical industry.

Workflows and performances in the ranking prediction of 2016 D3R Grand Challenge 2: lessons learned from a collaborative effort.

The 2016 D3R Grand Challenge 2 includes both pose and affinity or ranking predictions. This article is focused exclusively on affinity predictions submitted to the D3R challenge from a collaborative effort of the modeling and informatics group. Our submissions include ranking of 102 ligands covering 4 different chemotypes against the FXR ligand binding domain structure, and the relative binding affinity predictions of the two designated free energy subsets of 15 and 18 compounds.

Performance of multiple docking and refinement methods in the pose prediction D3R prospective Grand Challenge 2016.

We describe the performance of multiple pose prediction methods for the D3R 2016 Grand Challenge. The pose prediction challenge includes 36 ligands, which represent 4 chemotypes and some miscellaneous structures against the FXR ligand binding domain. In this study we use a mix of fully automated methods as well as human-guided methods with considerations of both the challenge data and publicly available data.

Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite λ Dynamics.

Multisite λ dynamics (MSλD) is a powerful emerging method in free energy calculation that allows prediction of relative free energies for a large set of compounds from very few simulations. Calculating free energy differences between substituents that constitute large volume or flexibility jumps in chemical space is difficult for free energy methods in general, and for MSλD in particular, due to large free energy barriers in alchemical space. This study demonstrates that a simple biasing potential can flatten these barriers and introduces an algorithm that determines system specific biasing potential coefficients.

Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2).

Post-translational S-palmitoylation directs the trafficking and membrane localization of hundreds of cellular proteins, often involving a coordinated palmitoylation cycle that requires both protein acyl transferases (PATs) and acyl protein thioesterases (APTs) to actively redistribute S-palmitoylated proteins toward different cellular membrane compartments. This process is necessary for the trafficking and oncogenic signaling of S-palmitoylated Ras isoforms, and potentially many peripheral membrane proteins. The depalmitoylating enzymes APT1 and APT2 are separately conserved in all vertebrates, suggesting unique functional roles for each enzyme.

Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand-protein interactions.

A halogen bond is a highly directional, non-covalent interaction between a halogen atom and another electronegative atom. It arises due to the formation of a small region of positive electrostatic potential opposite the covalent bond to the halogen, called the 'sigma hole.' Empirical force fields in which the electrostatic interactions are represented by atom-centered point charges cannot capture this effect because halogen atoms usually carry a negative charge and therefore interact unfavorably with other electronegative atoms.

Biasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations.

Traditional free energy calculation methods are well-known for their drawbacks in scalability and speed in converging results particularly for calculations with large perturbations. In the present work, we report on the development of biasing potential replica exchange multisite λ-dynamics (BP-REX MSλD), which is a free energy method that is capable of performing simultaneous alchemical free energy transformations, including perturbations between flexible moieties. BP-REX MSλD and the original MSλD are applied to a series of symmetrical 2,5-benzoquinone derivatives covering a diverse chemical space and range of conformational flexibility.