Sire: An interoperability engine for prototyping algorithms and exchanging information between molecular simulation programs.

Sire is a Python/C++ library that is used both to prototype new algorithms and as an interoperability engine for exchanging information between molecular simulation programs. It provides a collection of file parsers and information converters that together make it easier to combine and leverage the functionality of many other programs and libraries. This empowers researchers to use sire to write a single script that can, for example, load a molecule from a PDBx/mmCIF file via Gemmi, perform SMARTS searches via RDKit, parameterize molecules using BioSimSpace, run GPU-accelerated molecular dynamics via OpenMM, and then display the resulting dynamics trajectory in a NGLView Jupyter notebook 3D molecular viewer. This functionality is built on by BioSimSpace, which uses sire's molecular information engine to interconvert with programs such as GROMACS, NAMD, Amber, and AmberTools for automated molecular parameterization and the running of molecular dynamics, metadynamics, and alchemical free energy workflows. Sire comes complete with a powerful molecular information search engine, plus trajectory loading and editing, analysis, and energy evaluation engines. This, when combined with an in-built computer algebra system, gives substantial flexibility to researchers to load, search for, edit, and combine molecular information from multiple sources and use that to drive novel algorithms by combining functionality from other programs. Sire is open source (GPL3) and is available via conda and at a free Jupyter notebook server at https://try.openbiosim.org. Sire is supported by the not-for-profit OpenBioSim community interest company.

Hybrid Alchemical Free Energy/Machine-Learning Methodology for the Computation of Hydration Free Energies.

A methodology that combines alchemical free energy calculations (FEP) with machine learning (ML) has been developed to compute accurate absolute hydration free energies. The hybrid FEP/ML methodology was trained on a subset of the FreeSolv database and retrospectively shown to outperform most submissions from the SAMPL4 competition. Compared to pure machine-learning approaches, FEP/ML yields more precise estimates of free energies of hydration and requires a fraction of the training set size to outperform standalone FEP calculations. The ML-derived correction terms are further shown to be transferable to a range of related FEP simulation protocols. The approach may be used to inexpensively improve the accuracy of FEP calculations and to flag molecules which will benefit the most from bespoke force field parametrization efforts.

Assessment of Binding Affinity via Alchemical Free-Energy Calculations.

Free-energy calculations have seen increased usage in structure-based drug design. Despite the rising interest, automation of the complex calculations and subsequent analysis of their results are still hampered by the restricted choice of available tools. In this work, an application for automated setup and processing of free-energy calculations is presented. Several sanity checks for assessing the reliability of the calculations were implemented, constituting a distinct advantage over existing open-source tools. The underlying workflow is built on top of the software Sire, SOMD, BioSimSpace, and OpenMM and uses the AMBER 14SB and GAFF2.1 force fields. It was validated on two datasets originally composed by Schrödinger, consisting of 14 protein structures and 220 ligands. Predicted binding affinities were in good agreement with experimental values. For the larger dataset, the average correlation coefficient Rp was 0.70 ± 0.05 and average Kendall's τ was 0.53 ± 0.05, which are broadly comparable to or better than previously reported results using other methods.

A mechanistic hypothesis for the aspirin-induced switch in lipid mediator production by cyclooxygenase-2.

Cyclooxygenase (COX) carries out stereospecific oxygen addition to arachidonic acid to generate prostaglandins, plus smaller amounts of 11- and 15-hydroxyeicosatetraenoic acids. For COX-2, the stereochemistry and relative abundance of generated products is influenced by Ser530 acetylation following aspirin treatment. The molecular bases of the high degree of stereospecificity which characterizes COX-2-catalyzed oxygenations are not yet completely understood, nor are the reasons behind the aspirin-induced shift in lipid mediator production. A mechanistic hypothesis is proposed which identifies steric shielding as the main determinant of oxygenation stereospecificity. This hypothesis is supported by a computational model which accurately reproduces experimental oxygenation patterns on both native and aspirin-inhibited COX-2.

Design and Synthesis of a γ(1)ß(8)-Cyclodextrin Oligomer: A New Platform with Potential Application as a Dendrimeric Multicarrier.

We report the synthesis and characterization of a water-soluble, star-shaped macromolecular platform consisting of eight ß-cyclodextrin (ß-CD) units anchored to the narrower rim of a γ-CD core through bis(triazolyl)alkyl spacers. The efficient synthetic protocol is based on the microwave (MW)-promoted Cu-catalyzed 1,3-dipolar cycloaddition of CD monoazides to CD monoacetylenes. The ligand-hosting capability of the construct has been assessed by relaxometric titration and nuclear magnetic relaxation dispersion (NMRD) profiling, which showed it to be good, and this was supported by molecular dynamics simulations. To demonstrate the feasibility of obtaining supramolecular structures with high hosting ability, we designed a dimeric platform, formed by joining two nonamers through the γ-CD cores through a bis(lithocholic acid) linker. With a view to the potential biological applications, cytotoxicity and extent of binding to human serum albumin were assessed. The properties of this dendrimeric multicarrier make it suitable for pharmaceutical and diagnostic purposes, ranging from targeted drug delivery to molecular imaging.

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.

Thymopentin down-regulates both activity and expression of iNOS in blood cells of Sézary syndrome patients.

While thymopentin has been used for many years in the experimental treatment of Sézary syndrome (SS), a rare and very aggressive lymphoma, its mechanism of action is still not known. Herein we show that this peptide acts as an inhibitor of isolated iNOS and nNOS isoforms, and reduces iNOS protein/mRNA levels and iNOS activity in blood cells obtained from both healthy donors and SS patients. Similar results were obtained with TPN-2, the N(ω)-nitro analogue of the Arg-Lys motif present in thymopentin. Additional investigations are necessary to confirm the role and the relative importance of the two mechanisms of iNOS down-regulation in the therapeutic action of these peptides against SS.

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.

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.

Chemical Reactivity Prediction: Current Methods and Different Application Areas.

The ability to predict chemical reactivity of a molecule is highly desirable in drug discovery, both ex vivo (synthetic route planning, formulation, stability) and in vivo: metabolic reactions determine pharmacodynamics, pharmacokinetics and potential toxic effects, and early assessment of liabilities is vital to reduce attrition rates in later stages of development. Quantum mechanics offer a precise description of the interactions between electrons and orbitals in the breaking and forming of new bonds. Modern algorithms and faster computers have allowed the study of more complex systems in a punctual and accurate fashion, and answers for chemical questions around stability and reactivity can now be provided. Through machine learning, predictive models can be built out of descriptors derived from quantum mechanics and cheminformatics, even in the absence of experimental data to train on. In this article, current progress on computational reactivity prediction is reviewed: applications to problems in drug design, such as modelling of metabolism and covalent inhibition, are highlighted and unmet challenges are posed.

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.

Synthesis and preliminary pharmacological characterisation of a new class of nitrogen-containing bisphosphonates (N-BPs).

A new series of bisphosphonates bearing either the nitrogen-containing NO-donor furoxan (1,2,5-oxadiazole 2-oxide) system or the related furazan (1,2,5-oxadiazole) in lateral chain has been developed. pK(a) values and affinity for hydroxyapatite were determined for all the compounds. The products were able to inhibit osteoclastogenesis on RAW 246.7 cells at 10microM concentration. The most active compounds were further assayed on human PBMC cells and on rat microsomes. Unlike most nitrogen-containing bisphosphonates which target farnesyl pyrophosphate synthase, experimental and theoretical investigations suggest that the activity of our derivatives may be related to different mechanisms. The furoxan derivatives were also tested for their ability to relax rat aorta strips in view of their potential NO-dependent vasodilator properties.

Mucoepidermoid carcinoma of the lacrimal sac masquerading as dacryocystitis.

Tumors originating from the lacrimal sac are exceedingly rare. They may mimic chronic inflammation and be misdiagnosed, delaying treatment and allowing the tumor to devastate the visual system. Mucoepidermoid carcinoma has been described only occasionally. We report a case that presented with unusual diagnostic and treatment aspects. A 33-year-old Italian man had tearing in his right eye. The initial presentation mimicked dacryocystitis, and the patient had been treated with antibiotics and steroids, without results. Consequently, an external dacryocystorhinostomy was performed, during which an open biopsy specimen was taken; it suggested the presence of a basocellular epithelioma. Computed tomography, magnetic resonance imaging, and further biopsies led to the diagnosis of squamous carcinoma of the lacrimal sac. On this basis, the patient underwent preoperative radiation (41.4 Gy) and conservative surgical resection of the tumor, with preservation of the eye and extraocular muscles. The histopathologic examination of the gross surgical specimen led to a final diagnosis of primary mucoepidermoid carcinoma of the lacrimal sac and revealed clear resection margins. The clinical evaluation and positron emission tomography at 6 months showed complete functional recovery and no evidence of the disease. This report highlights the clinicopathologic characteristics and therapeutic uncertainty of this rare tumor.

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.

NO-donor COX-2 inhibitors. New nitrooxy-substituted 1,5-diarylimidazoles endowed with COX-2 inhibitory and vasodilator properties.

A series of NO-donor diarylimidazoles derived from the lead compound Cimicoxib were synthesized and evaluated for their COX-2 inhibitory activity and their stability in whole blood as well as for vasodilator properties. The products are partly transformed into the corresponding alcohols following 24-h incubation in whole blood. All of them display good COX-1/COX-2 selectivity, but are less potent than the lead; a molecular modeling study was carried out to investigate their binding mode. The compounds are also capable of relaxing rat aorta strips precontracted with phenylephrine with a NO-dependent mechanism; this property could confer reduced cardiotoxicity with respect to traditional COX-2 inhibitors.

Non-imidazole histamine NO-donor H3-antagonists.

Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.

A new class of NO-donor H3-antagonists.

Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 microM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier.

Progressive midfacial bone erosion and necrosis: case report and differential diagnosis.

A 31-year-old woman presented with a large oro-nasal communication (ONC), loss of vomer and significant nasal cartilage and nose deformity. Physical examination of the patient revealed a typical midline destructive lesion (MDL) with nasal septum and hard/soft palate perforation with a friable granular surface and a large amount of necrotic tissues. Medical history was unremarkable and the patient denied previous local trauma, including surgical procedures or drug assumption. Pathological examination revealed the presence of necrosis and chronic inflammation. MDLs have numerous etiologies. Signs and symptoms of MDLs can be similar and an accurate diagnosis may be elusive. We hereby present detailed clinicopathological findings.

The role of fluorine in stabilizing the bioactive conformation of dihydroorotate dehydrogenase inhibitors.

Dihydroorotate dehydrogenase (DHODH) is an important drug target due to its prominent role in pyrimidine biosynthesis. Leflunomide and brequinar are two well-known DHODH inhibitors, which bind to the enzyme in the same pocket with different binding modes. We have recently realized a series of new inhibitors based on the 4-hydroxy-1,2,5-oxadiazole ring, whose activity profile was found to be closely dependent on the degree of fluorine substitution at the phenyl ring adjacent to the oxadiazole moiety; a positive influence of fluorine on the DHODH inhibitory potency was observed previously [Baumgartner et al. (2006) J Med Chem 49:1239-1247]. Potential energy surface scans showed that fluorine plays an important role in stabilizing the bioactive conformations; additionally, fluorine influences the balance between leflunomide-like and brequinar-like binding modes. These findings may serve as a guide to design more potent DHODH inhibitors.

6-Cyclohexylmethoxy-5-(cyano-NNO-azoxy)pyrimidine-4-amine: a new scaffold endowed with potent CDK2 inhibitory activity.

Substitution of the cyano-NNO-azoxy moiety (NC-N=(O)N-) for the nitroso group in NU6027, a potent and selective CDK2 inhibitor, affords a compound with slightly improved potency and comparable selectivity profile. A molecular modelling study indicates for this new scaffold a binding mode similar to the one adopted by other purine and pyrimidine analogues, and suggests a relevant role for a conserved water molecule in stabilizing the bioactive pose of this and other pyrimidine ligands. The introduction of aminosulfonylphenyl substituents on the 2-amino group of the pyrimidine increased the CDK2 inhibitory potency by two orders of magnitude, while maintaining the same degree of selectivity.