2 research outputs found
Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study
Binding
free energies of bromodomain inhibitors are calculated
with recently formulated approaches, namely ESMACS (enhanced sampling
of molecular dynamics with approximation of continuum solvent) and
TIES (thermodynamic integration with enhanced sampling). A set of
compounds is provided by GlaxoSmithKline, which represents a range
of chemical functionality and binding affinities. The predicted binding
free energies exhibit a good Spearman correlation of 0.78 with the
experimental data from the 3-trajectory ESMACS, and an excellent correlation
of 0.92 from the TIES approach where applicable. Given access to suitable
high end computing resources and a high degree of automation, we can
compute individual binding affinities in a few hours with precisions
no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and
1.71 kcal/mol for the 1- and 3-trajectory ESMACS approaches
Optimization of Sphingosine-1-phosphate‑1 Receptor Agonists: Effects of Acidic, Basic, and Zwitterionic Chemotypes on Pharmacokinetic and Pharmacodynamic Profiles
The efficacy of the recently approved
drug fingolimod (FTY720)
in multiple sclerosis patients results from the action of its phosphate
metabolite on sphingosine-1-phosphate S1P<sub>1</sub> receptors, while
a variety of side effects have been ascribed to its S1P<sub>3</sub> receptor activity. Although S1P and phospho-fingolimod share the
same structural elements of a zwitterionic headgroup and lipophilic
tail, a variety of chemotypes have been found to show S1P<sub>1</sub> receptor agonism. Here we describe a study of the tolerance of the
S1P<sub>1</sub> and S1P<sub>3</sub> receptors toward bicyclic heterocycles
of systematically varied shape and connectivity incorporating acidic,
basic, or zwitterionic headgroups. We compare their physicochemical
properties, their performance in <i>in vitro</i> and <i>in vivo</i> pharmacokinetic models, and their efficacy in peripheral
lymphocyte lowering. The campaign resulted in the identification of
several potent S1P<sub>1</sub> receptor agonists with good selectivity
vs S1P<sub>3</sub> receptors, efficacy at <1 mg/kg oral doses,
and developability properties suitable for progression into preclinical
development