39 research outputs found
Efficient Transition State Modeling Using Molecular Mechanics Force Fields for the Everyday Chemist
No full text
Customizable Generation of Synthetically Accessible, Local Chemical Subspaces
No full textScreening
large libraries of chemicals has been an efficient strategy
to discover bioactive compounds; however a portion of the potential
for success is limited to the available libraries. Synergizing combinatorial
and computational chemistries has emerged as a time-efficient strategy
to explore the chemical space more widely. Ideally, streamlining the
evaluation process for larger, feasible chemical libraries would become
commonplace. Thus, combinatorial tools and, for example, docking methods
would be integrated to identify novel bioactive entities. The idea
is simple in nature, but much more complex in practice; combinatorial
chemistry is more than the coupling of chemicals into products: synthetic
feasibility includes chemoselectivity, stereoselectivity, protecting
group chemistry, and chemical availability which must all be considered
for combinatorial library design. In addition, intuitive interfaces
and simple user manipulation is key for optimal use of such tools
by organic chemistscrucial for the integration of such software
in medicinal chemistry laboratories. We present herein Finders and React2Dintegrated into the Virtual Chemist platform, a modular software suite. This approach
enhances virtual combinatorial chemistry by identifying available
chemicals compatible with a user-defined chemical transformation and
by carrying out the reaction leading to libraries of realistic, synthetically
accessible chemicalsall with a completely automated, black-box,
and efficient design. We demonstrate its utility by generating ∼40
million synthetically accessible, stereochemically accurate compounds
from a single library of 100 000 purchasable molecules and
56 well-characterized chemical reactions
Single-Point Mutation with a Rotamer Library Toolkit: Toward Protein Engineering
No full textProtein engineers
have long been hard at work to harness biocatalysts
as a natural source of regio-, stereo-, and chemoselectivity in order
to carry out chemistry (reactions and/or substrates) not previously
achieved with these enzymes. The extreme labor demands and exponential
number of mutation combinations have induced computational advances
in this domain. The first step in our virtual approach is to predict
the correct conformations upon mutation of residues (i.e., rebuilding
side chains). For this purpose, we opted for a combination of molecular
mechanics and statistical data. In this work, we have developed automated
computational tools to extract protein structural information and
created conformational libraries for each amino acid dependent on
a variable number of parameters (e.g., resolution, flexibility, secondary
structure). We have also developed the necessary tool to apply the
mutation and optimize the conformation accordingly. For side-chain
conformation prediction, we obtained overall average root-mean-square
deviations (RMSDs) of 0.91 and 1.01 Å for the 18 flexible natural
amino acids within two distinct sets of over 3000 and 1500 side-chain
residues, respectively. The commonly used dihedral angle differences
were also evaluated and performed worse than the state of the art.
These two metrics are also compared. Furthermore, we generated a family-specific
library for kinases that produced an average 2% lower RMSD upon side-chain
reconstruction and a residue-specific library that yielded a 17% improvement.
Ultimately, since our protein engineering outlook involves using our
docking software, Fitted/Impacts, we applied our
mutation protocol to a benchmarked data set for self- and cross-docking.
Our side-chain reconstruction does not hinder our docking software,
demonstrating differences in pose prediction accuracy of approximately
2% (RMSD cutoff metric) for a set of over 200 protein/ligand structures.
Similarly, when docking to a set of over 100 kinases, side-chain reconstruction
(using both general and biased conformation libraries) had minimal
detriment to the docking accuracy
Book review: The pub in literature, by Steven Earnshaw
No full text‘The conviviality of the narrative premise’ is Steven Earnshaw’s felicitous phrase for the theme that suffuses this book. It is ‘a crawl through the drinking places of English literary history,’ in the company of Chaucer, Langland, Shakespeare, Dekker, Jonson, Pepys, Ned Ward (author of The London Spy), Goldsmith, Gray, Fielding, Cowper, Crabbe, Dickens, Eliot (G.), Hardy, Eliot (T. S.), Coppard, Hampson, Hamilton, Orwell and Amis (M.). It also ‘attempts to weave a pattern out of the strands of “pub”, English literature and England’. It is a labour of love, the product of years of hoarded references and inspired cups and we must be grateful. It will become a standard resort for literary scholars seeking quotable material on pubs (Piers Plowman ‘pissed a pottel in a pater-noster while’), and for anyone who likes to savour ‘the pub moment’ through the medium of print
Highly Regioselective Monoacylation of Unprotected Glucopyranoside Using Transient Directing‐Protecting Groups
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Docking Ligands into Flexible and Solvated Macromolecules. 6. Development and Application to the Docking of HDACs and other Zinc Metalloenzymes Inhibitors
No full textThe Recognition of Unrelated Ligands by Identical Proteins
No full textUnrelated
ligands, often found in drug discovery campaigns, can
bind to the same receptor, even with the same protein residues. To
investigate how this might occur, and whether it might be typically
possible to find unrelated ligands for the same drug target, we sought
examples of topologically unrelated ligands that bound to the same
protein in the same site. Seventy-six pairs of ligands, each bound
to the same protein (152 complexes total), were considered, classified
into three groups. In the first (31 pairs of complexes), unrelated
ligands interacted largely with the same pocket residues through different
functional groups. In the second group (39 pairs), the unrelated ligand
in each pair engaged different residues, though still within the same
pocket. The smallest group (6 pairs) contained ligands with different
scaffolds but with shared functional groups interacting with the same
residues. We found that there are multiple chemically unrelated but
physically similar functional groups that can complement any given
local protein pocket; when these functional group substitutions are
combined within a single molecule, they lead to topologically unrelated
ligands that can each well-complement a site. It may be that many
active and orthosteric sites can recognize topologically unrelated
ligands
