Paolo Tosco

Open3DQSAR: a new open-source software aimed at high-throughput chemometric analysis of molecular interaction fields

AbstractOpen3DQSAR is a freely available open-source program aimed at chemometric analysis of molecular interaction fields. MIFs can be imported from different sources (GRID, CoMFA/CoMSIA, quantum-mechanical electrostatic potential or electron density grids) or generated by Open3DQSAR itself. Much focus has been put on automation through the implementation of a scriptable interface, as well as on high computational performance achieved by algorithm parallelization. Flexibility and interoperability with existing molecular modeling software make Open3DQSAR a powerful tool in pharmacophore assessment and ligand-based drug design. FigureOpen3DQSAR’s logo displaying PLS coefficient isocontours

Open3DALIGN: an open-source software aimed at unsupervised ligand alignment

An open-source, cross-platform software aimed at conformer generation and unsupervised rigid-body molecular alignment is presented. Different algorithms have been implemented to perform single and multi-conformation superimpositions on one or more templates. Alignments can be accomplished by matching pharmacophores, heavy atoms or a combination of the two. All methods have been successfully validated on eight comprehensive datasets previously gathered by Sutherland and co-workers. High computational performance has been attained through efficient parallelization of the code. The unsupervised nature of the alignment algorithms, together with its scriptable interface, make Open3DALIGN an ideal component of high-throughput, automated cheminformatics workflows.

Surgical treatment and reconstruction for central giant cell granuloma of the jaws: A review of 18 cases

Central giant cell granuloma (CGCG) is an uncommon benign bony lesion that occurs in the mandible and maxilla. The clinical behaviour of CGCG ranges from a slow-growing asymptomatic swelling to an aggressive lesion that presents pain, local bone destruction, root resorption and tooth displacement. Therapeutic options have varied greatly over the years. Non-surgical treatments with alpha interferon (alpha-IFN), calcitonin and corticosteroids have been described and their benefits may be worthy of consideration. Surgery is considered the traditional treatment and it is still the most accepted one, however in the literature not all authors agree on the type of surgery which should be performed. Although en bloc resection provides the lowest recurrence rate, only a few single case reports describe the use of this technique followed by reconstruction with autogenous bone grafts. The authors report their experience with en bloc resection of 18 wide CGCGs which had not been previously treated medically. Immediate reconstruction was carried out for all cases and in one, a fibula free flap was used to reconstruct the mandible. No recurrence was observed. After complete healing of the graft, prosthetic rehabilitation via implants was performed. This allowed the best functional and aesthetic results.

Long-term clinical and radiological outcomes for the surgical treatment of mandibular condylar fractures.

PURPOSE This retrospective study evaluated the long-term results and complications of open reduction and internal fixation of displaced and dislocated fractures of the condylar process. PATIENTS AND METHODS Two hundred four patients were treated via various surgical approaches between 1991 and 2005. Fifty patients with a total of 57 treated condylar fractures who underwent complete clinical and radiological documentation were included in this study. Follow-up clinical and radiological evaluations were carried out after an average period of 88 months. RESULTS We found that 12% of our patients reported temporary weakness of the facial nerve and 4% had mild permanent facial nerve palsy. Clinical and radiological assessment showed satisfactory recovery of facial symmetry. Excellent recovery of function was observed, and very few patients complained of temporomandibular joint-related symptoms. Severe condylar remodeling was observed in 8% of the patients, 47% showed slight or moderate remodeling, and 45% showed no remodeling. A statistically significant association was observed between the presence of condylar remodeling and poor mouth opening at the follow-up examination. CONCLUSIONS Surgical treatment of condylar fractures, in association with postoperative functional therapy, promotes the recovery of function, occlusion, and facial symmetry with few complications. However, some difficulties remain related to the surgeon, the patient, and the objective complexity of this pathology.

Novel small molecule protein arginine deiminase 4 (PAD4) inhibitors

Protein arginin deaminase 4 (PAD4) is a calcium dependent enzyme which catalyses the conversion of peptidyl-arginine into peptidyl-citrulline and is implicated in several diseases such as rheumatoid arthritis (RA) and cancer. Herein we report the discovery of novel small-molecule, non peptidic PAD4 inhibitors incorporating primary/secondary guanidine moieties.

Edaravone derivatives containing NO-donor functions.

A new series of polyvalent drugs obtained by joining edaravone with NO-donor moieties is described. All compounds display high antioxidant power together with NO-dependent vasodilator properties. The analysis of a number of molecular descriptors shows that the antioxidant activity, which is tightly linked to the presence of the edaravone substructure, is principally modulated by lipophilicity. These products are potentially useful in the treatment of cardiovascular disorders in which EDRF deficiency and ROS excess are involved.

Mechanistic insights into cyclooxygenase irreversible inactivation by aspirin.

A mechanistic hypothesis for the acetylation of cyclooxygenase (COX) by aspirin is proposed on the basis of a QM/MM study. This mechanism is consistent with previous experimental findings by other investigators. Ser 530 appears to be acetylated under intramolecular general base catalysis provided by the carboxylate moiety of aspirin, while Tyr 385 plays a crucial role in orienting and polarizing the acetyl group.

[3-(1H-imidazol-4-yl)propyl]guanidines containing furoxan moieties: A new class of H3-Antagonists endowed with NO-donor properties

Synthesis and pharmacological characterisation of a series of products obtained by coupling the H(3)-antagonist SKF 91486 through appropriate spacers with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan substructures, devoid of NO-donating properties, are reported. All the products were tested for their H(3)-antagonistic and H(2)-agonistic properties on electrically-stimulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. The whole series of compounds displayed good H(3)-antagonist behaviour and feeble partial H(2)-agonist activity. Among furoxan derivatives, the benzenesulfonyl hybrid 28, a good NO-donor, triggered a dual NO-dependent muscle relaxation and H(3)-antagonistic effect on guinea-pig intestine.

COSMOsar3D: molecular field analysis based on local COSMO σ-profiles.

The COSMO surface polarization charge density σ resulting from quantum chemical calculations combined with a virtual conductor embedding has been widely proven to be a very suitable descriptor for the quantification of interactions of molecules in liquids. In a preceding paper, grid-based local histograms of σ have been introduced in the COSMOsim3D method, resulting in a novel 3D-molecular similarity measure and going along with a novel property-based molecular alignment method. In this paper, we introduce under the name COSMOsar3D the usage of the resulting array of local σ-profiles as a novel set of molecular interaction fields for 3D-QSAR, containing all information required for quantifying the virtual ligand-receptor interactions, including desolvation. In contrast to currently used molecular interaction fields, we provide a theoretical rationale that the logarithmic binding constants of ligands should be a linear function of the array of local σ-profiles. This makes them especially suitable for linear regression analysis methods such as PLS. We demonstrate that the usage of local σ-profiles in molecular field analysis inverts the role of ligands and receptor; while conventional 3D-QSAR considers the virtual receptor in potential energy fields provided by the ligands, our COSMOsar3D approach corresponds to the calculation of the free energy of the ligands in a virtual free energy field provided by the receptor. First applications of the COSMOsar3D method are presented, which demonstrate its ability to yield robust and predictive models that seem to be superior to the models generated on the basis of conventionally used molecular fields.

A 3D-QSAR-Driven Approach to Binding Mode and Affinity Prediction

A method for predicting the binding mode of a series of ligands is proposed. The procedure relies on three-dimensional quantitative structure-activity relationships (3D-QSAR) and does not require structural knowledge of the binding site. Candidate alignments are automatically built and ranked according to a consensus scoring function. 3D-QSAR analysis based on the selected binding mode enables affinity prediction of new drug candidates having less than 10 rotatable bonds.