The SAMPL6 SAMPLing challenge: assessing the reliability and efficiency of binding free energy calculations.

Approaches for computing small molecule binding free energies based on molecular simulations are now regularly being employed by academic and industry practitioners to study receptor-ligand systems and prioritize the synthesis of small molecules for ligand design. Given the variety of methods and implementations available, it is natural to ask how the convergence rates and final predictions of these methods compare. In this study, we describe the concept and results for the SAMPL6 SAMPLing challenge, the first challenge from the SAMPL series focusing on the assessment of convergence properties and reproducibility of binding free energy methodologies.

Effect of set up protocols on the accuracy of alchemical free energy calculation over a set of ACK1 inhibitors.

Hit-to-lead virtual screening frequently relies on a cascade of computational methods that starts with rapid calculations applied to a large number of compounds and ends with more expensive computations restricted to a subset of compounds that passed initial filters. This work focuses on set up protocols for alchemical free energy (AFE) scoring in the context of a Docking-MM/PBSA-AFE cascade. A dataset of 15 congeneric inhibitors of the ACK1 protein was used to evaluate the performance of AFE set up protocols that varied in the steps taken to prepare input files (using previously docked and best scored poses, manual selection of poses, manual placement of binding site water molecules).

Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages.

Alchemical free energy calculations are an increasingly important modern simulation technique to calculate free energy changes on binding or solvation. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS, and SOMD include support for the method. Implementation details vary among those codes, but users expect reliability and reproducibility, i.

Blinded predictions of standard binding free energies: lessons learned from the SAMPL6 challenge.

In the context of the SAMPL6 challenges, series of blinded predictions of standard binding free energies were made with the SOMD software for a dataset of 27 host-guest systems featuring two octa-acids hosts (OA and TEMOA) and a cucurbituril ring (CB8) host. Three different models were used, ModelA computes the free energy of binding based on a double annihilation technique; ModelB additionally takes into account long-range dispersion and standard state corrections; ModelC additionally introduces an empirical correction term derived from a regression analysis of SAMPL5 predictions previously made with SOMD. The performance of each model was evaluated with two different setups; buffer explicitly matches the ionic strength from the binding assays, whereas no-buffer merely neutralizes the host-guest net charge with counter-ions.

Metabolism and hydrophilicity of the polarised 'Janus face' all- tetrafluorocyclohexyl ring, a candidate motif for drug discovery.

The metabolism and polarity of the all- tetra-fluorocyclohexane motif is explored in the context of its potential as a motif for inclusion in drug discovery programmes. Biotransformations of phenyl all- tetra-, tri- and di- fluoro cyclohexanes with the human metabolism model organism illustrates various hydroxylated products, but limited to benzylic hydroxylation for the phenyl all- tetrafluorocyclohexyl ring system. Evaluation of the lipophilicities (log ) indicates a significant and progressive increase in polarity with increasing fluorination on the cyclohexane ring system.

Blinded predictions of distribution coefficients in the SAMPL5 challenge.

In the context of the SAMPL5 challenge water-cyclohexane distribution coefficients for 53 drug-like molecules were predicted. Four different models based on molecular dynamics free energy calculations were tested. All models initially assumed only one chemical state present in aqueous or organic phases.

Blinded predictions of host-guest standard free energies of binding in the SAMPL5 challenge.

In the context of the SAMPL5 blinded challenge standard free energies of binding were predicted for a dataset of 22 small guest molecules and three different host molecules octa-acids (OAH and OAMe) and a cucurbituril (CBC). Three sets of predictions were submitted, each based on different variations of classical molecular dynamics alchemical free energy calculation protocols based on the double annihilation method. The first model (model A) yields a free energy of binding based on computed free energy changes in solvated and host-guest complex phases; the second (model B) adds long range dispersion corrections to the previous result; the third (model C) uses an additional standard state correction term to account for the use of distance restraints during the molecular dynamics simulations.

Developmental toxicity, uptake and distribution of sodium chromate assayed by frog embryo teratogenesis assay-Xenopus(FETAX).

The embryotoxicity and teratogenicity of Cr(VI) on the survival and morphology of the anuran Xenopus laevis have been assessed by frog embryo teratogenesis assay-Xenopus (FETAX). The lethal median (LC(50)) and teratogenic median (TC(50)) concentration values of Cr(VI) were 890 microM and 260 microM, respectively. The calculated teratogenic index (TI) value was 3.

Arsenic toxicity and HSP70 expression in Xenopus laevis embryos.

The evaluation of the effect of trace metals on health can be difficult, because of their presence in the environment in various chemical forms. Exposure to arsenic compounds is an example of this complexity, as it can be present in the environment in inorganic and organic forms. The effects of arsenic in vertebrates are complicated by several variables, such as speciation of the element, the exposure route, and the susceptibility of the particular animal species.