6 research outputs found
Optimal affinity ranking for automated virtual screening validated in prospective D3R grand challenges
The goal of virtual screening is to generate a substantially reduced and enriched subset of compounds from a large virtual chemistry space. Critical in these efforts are methods to properly rank the binding affinity of compounds. Prospective evaluations of ranking strategies in the D3R grand challenges show that for targets with deep pockets the best correlations (Spearman rho similar to 0.5) were obtained by our submissions that docked compounds to the holo-receptors with the most chemically similar ligand. On the other hand, for targets with open pockets using multiple receptor structures is not a good strategy. Instead, docking to a single optimal receptor led to the best correlations (Spearman rho similar to 0.5), and overall performs better than any other method. Yet, choosing a suboptimal receptor for crossdocking can significantly undermine the affinity rankings. Our submissions that evaluated the free energy of congeneric compounds were also among the best in the community experiment. Error bars of around 1 kcal/mol are still too large to significantly improve the overall rankings. Collectively, our top of the line predictions show that automated virtual screening with rigid receptors perform better than flexible docking and other more complex methods
Fidelity, Mismatch Extension, and Proofreading Activity of the <i>Plasmodium falciparum</i> Apicoplast DNA Polymerase
<i>Plasmodium falciparum</i>, a parasitic organism and
one of the causative agents of malaria, contains an unusual organelle
called the apicoplast. The apicoplast is a nonphotosynthetic plastid
responsible for supplying the parasite with isoprenoid units and is
therefore indispensable. Like mitochondria and the chloroplast, the
apicoplast contains its own genome and harbors the enzymes responsible
for its replication. In this report, we determine the relative probabilities
of nucleotide misincorporation by the apicoplast polymerase (apPOL),
examine the kinetics and sequence dependence of mismatch extension,
and determine the rates of mismatch removal by the 3′ to 5′
proofreading activity of the DNA polymerase. While the intrinsic polymerase
fidelity varies by >50-fold for the 12 possible nucleotide misincorporations,
the most dominant selection step for overall polymerase fidelity is
conducted at the level of mismatch extension, which varies by >350-fold.
The efficiency of mismatch extension depends on both the nature of
the DNA mismatch and the templating base. The proofreading activity
of the 12 possible mismatches varies <3-fold. The data for these
three determinants of polymerase-induced mutations indicate that the
overall mutation frequency of apPOL is highly dependent on both the
intrinsic fidelity of the polymerase and the identity of the template
surrounding the potential mismatch