6 research outputs found
4-Pregnen-21-ol-3,20-dione-21-(4-bromobenzenesulfonate) (NSC 88915) and related novel steroid derivatives as tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an enzyme that catalyzes the hydrolysis of 3'-phosphotyrosyl bonds. Such linkages form in vivo when topoisomerase I (Top1) processes DNA. For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes. Tdp1 inhibitors have been regarded as potential therapeutics in combination with Top1 inhibitors, such as the camptothecin derivatives, topotecan and irinotecan, which are used to treat human cancers. Using a novel high-throughput screening assay, we have identified the C21-substituted progesterone derivative, NSC 88915 (1), as a potential Tdp1 inhibitor. Secondary screening and cross-reactivity studies with related DNA processing enzymes confirmed that compound 1 possesses specific Tdp1 inhibitory activity. Deconstruction of compound 1 into discrete functional groups reveals that both components are required for inhibition of Tdp1 activity. Moreover, the synthesis of analogues of compound 1 has provided insight into the structural requirements for the inhibition of Tdp1. Surface plasmon resonance shows that compound 1 binds to Tdp1, whereas an inactive analogue fails to interact with the enzyme. Based on molecular docking and mechanistic studies, we propose that these compounds are competitive inhibitors, which mimics the oligonucleotide-peptide Tdp1 substrate. These steroid derivatives represent a novel chemotype and provide a new scaffold for developing small molecule inhibitors of Tdp1
Development and Implementation of (Q)SAR Modeling Within the CHARMMing Web-user Interface
Recent availability of large publicly accessible databases of chemical compounds and their biological activities (PubChem, ChEMBL) has inspired us to develop a web-based tool for structure activity relationship and quantitative structure activity relationship modeling to add to the services provided by CHARMMing (www.charmming.org). This new module implements some of the most recent advances in modern machine learning algorithmsâRandom Forest, Support Vector Machine, Stochastic Gradient Descent, Gradient Tree Boosting, so forth. A user can import training data from Pubchem Bioassay data collections directly from our interface or upload his or her own SD files which contain structures and activity information to create new models (either categorical or numerical). A user can then track the model generation process and run models on new data to predict activity. Š 2014 Wiley Periodicals, Inc
Inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1) developed by virtual screening using ligand-based pharmacophores
PDB Ligand Conformational Energies Calculated Quantum-Mechanically
We present here a greatly updated version of an earlier
study on the conformational energies of proteinâligand complexes
in the Protein Data Bank (PDB) [Nicklaus et al. <i>Bioorg. Med.
Chem</i>. <b>1995</b>, <i>3</i>, 411â428],
with the goal of improving on all possible aspects such as number
and selection of ligand instances, energy calculations performed,
and additional analyses conducted. Starting from about 357,000 ligand
instances deposited in the 2008 version of the Ligand Expo database
of the experimental 3D coordinates of all small-molecule instances
in the PDB, we created a âhigh-qualityâ subset of ligand
instances by various filtering steps including application of crystallographic
quality criteria and structural unambiguousness. Submission of 640
Gaussian 03 jobs yielded a set of about 415 successfully concluded runs.
We used a stepwise optimization of internal degrees of freedom at
the DFT level of theory with the B3LYP/6-31GÂ(d) basis set and a single-point
energy calculation at B3LYP/6-311++GÂ(3df,2p) after each round of (partial)
optimization to separate energy changes due to bond length stretches
vs bond angle changes vs torsion changes. Even for the most âconservativeâ
choice of all the possible conformational energiesî¸the energy
difference between the conformation in which all internal degrees
of freedom except torsions have been optimized and the fully optimized
conformerî¸significant energy values were found. The range of
0 to âź25 kcal/mol was populated quite evenly and independently
of the crystallographic resolution. A smaller number of âoutliersâ
of yet higher energies were seen only at resolutions above 1.3 Ă
.
The energies showed some correlation with molecular size and flexibility
but not with crystallographic quality metrics such as the Cruickshank
diffraction-component precision index (DPI) and R<sub>free</sub>-R,
or with the ligand instance-specific metrics such as occupancy-weighted
B-factor (OWAB), real-space R factor (RSR), and real-space correlation
coefficient (RSCC). We repeated these calculations with the solvent
model IEFPCM, which yielded energy differences that were generally
somewhat lower than the corresponding vacuum results but did not produce
a qualitatively different picture. Torsional sampling around the crystal
conformation at the molecular mechanics level using the MMFF94s force
field typically led to an increase in energy