Biomedical subjects

Eric Arnoult

Publications and source records attributed to Eric Arnoult.

3 recordsLinked to original sources

PubMed2005

Optimization and validation of a docking-scoring protocol; application to virtual screening for COX-2 inhibitors.

To exploit available structural information about the cyclooxygenase enzyme for the virtual screening of large chemical libraries, a docking-scoring protocol was tuned and validated. The screening accuracy was assessed using a series of known inhibitors and a set of diverse a priori inactive compounds that was seeded with known active ligands. The major parameters of the DOCK algorithm were investigated. A large improvement of the results was obtained on tweaking some of them. The generated complexes were rescored using six scoring functions. In this way, the striking importance of this step was demonstrated, as well as the good performances of DOCK energy and SCORE for this target. The results were further improved via a consensus approach. As a first application, a subset of a large compound library was screened using this protocol. Among the compounds that were selected for biological testing, a third of them turned out to have a significant enzyme inhibition.

Crystallography, X-Ray↗

PubMed2002

HIV-1(Lai) genomic RNA: combined used of NMR and molecular dynamics simulation for studying the structure and internal dynamics of a mutated SL1 hairpin.

The genome of all retroviruses consists of two identical copies of an RNA sequence associated in a non-covalent dimer. A region upstream from the splice donor (SL1) comprising a self-complementary sequence is responsible for the initiation of the dimerization. This region is able to dimerize in two conformations: a loop-loop complex or an extended duplex. Here, we solve by 2D NMR techniques the solution structure of a 23-nucleotide sequence corresponding to HIV-1 SL1(Lai) in which the mutation G12-->A12 is included to prevent dimerization. It is shown that this monomer adopts a stem-loop conformation with a seven base pairs stem and a nine nucleotide loop containing the G10 C11 A12 C13 G14 C15 sequence. The stem is well structured in an A-form duplex, while the loop is more flexible even though elements of structure are evident. We show that the structure adopted by the stem can be appreciably different from its relaxed structure when the adenines A8, A9 and A16 in the loop are mechanically constrained. This point could be important for the efficiency of the dimerization. This experimental study is complemented with a 10 ns molecular dynamics simulation in the presence of counterions and explicit water molecules. This simulation brings about information on the flexibility of the loop, such as a hinge motion between the stem and the loop and a labile lattice of hydrogen bonds in the loop. The bases of the nucleotides G10 to C15 were found outside of the loop during a part of the trajectory, which is certainly necessary to initiate the dimerization process of the genuine SL1(Lai) sequence.

Base Sequence↗

PubMedDate not supplied

2D QSAR consensus prediction for high-throughput virtual screening. An application to COX-2 inhibition modeling and screening of the NCI database.

Using classification (SOM, LVQ, Binary, Decision Tree) and regression algorithms (PLS, BRANN, k-NN, Linear), this paper details the building of eight 2D-QSAR models from a 266 COX-2 inhibitor training set. The predictive performances of these eight models were subsequently compared using an 88 COX-2 inhibitor test set. Each ligand is described by 52 2D descriptors expressed as van der Waals Surface Areas (P_VSA) and its COX-2 binding IC50. One of our best predictive models is the neural network model (BRANN), which is able to select a subset, from the 88 ligand test set, that contains 94% COX-2 active inhibitors (pIC50>7.5) and detects 71% of all the actives. We then introduce a QSAR consensus prediction protocol that is shown to be more predictive than any single QSAR model: our C3 consensus approach is able to select a subset from the 88 ligand test set that contains 94% active inhibitors and 83% of all the actives. The 2D QSAR consensus protocol was finally applied to the high-throughput virtual screening of the NCI database, containing 193,477 organic compounds.

Cyclooxygenase 2↗