Visual attention patterns during a gaze following task in neurogenetic syndromes associated with unique profiles of autistic traits: Fragile X and Cornelia de Lange syndromes.

BACKGROUND: Gaze following difficulties are considered an early marker of autism, thought likely to cumulatively impact the development of social cognition, language and social skills. Subtle differences in gaze following abilities may contribute to the diverse range social and communicative autistic characteristics observed across people with genetic syndromes, such as Cornelia de Lange (CdLS) and fragile X (FXS) syndromes. AIMS: To compare profiles of 1) visual attention to the eye region at critical points of the attention direction process, 2) whether children follow the gaze cue to the object, and 3) participant looking time to the target object following the gaze cue between groups and conditions. MATERIALS AND METHODS: Children with CdLS (N = 11) and FXS (N = 8) and autistic (N = 22) and neurotypical (N = 15) children took part in a passive viewing paradigm adapted from Senju and Csibra (2008), in which videos of a central cue (ball/cartoon face/human face) directed attention towards one of two objects. Visual attention patterns were recorded via eye tracking technology. RESULTS: Neurotypical children were used as a reference group against which the autistic, CdLS and FXS groups were compared. Although autistic children looked at the eye region for significantly less time, they looked at the target object as frequently and for a similar duration as neurotypical children. Children with FXS looked at the target as frequently as neurotypical children but looked at it for comparatively less time. Both neurotypical children and children with CdLS frequently looked at the eye region, but children with CdLS were less likely to look at the target than neurotypical children. CONCLUSIONS: Findings provide preliminary evidence of unique patterns of visual attention and gaze following strategies in children with CdLS, children with FXS and autistic children. These unique gaze following patterns may underpin the distinct profiles of social and communication autistic traits observed between these groups.

Computer-aided identification of human carbonic anhydrase isoenzyme VII inhibitors as potential antiepileptic agents.

Human carbonic anhydrase (hCA) belongs to a superfamily of metalloenzymes that reversibly catalyse the hydration of carbon dioxide to give bicarbonate (HCO3-) and proton (H+). As HCO3- ions play an important role in neuronal signalling hence, hCA enzymes are an attractive target for antiepileptic drugs. Out of all the isoforms, hCA VII is predominantly expressed in the brain cortex and hippocampus region, which are the most affected area during seizure activity. Hence, we have identified some hCA VII inhibitors employing computational tools like atom-based 3D quantitative structure-activity relationship (QSAR), auto-QSAR, pharmacophore-based virtual screening, molecular docking, and molecular dynamics (MD) simulations. Atom-based 3D QSAR modelling outperformed auto-QSAR with an R2 and Q2 value of 0.9634 and 0.9646, respectively. A four-feature pharmacophore model (AADR_1) was developed and a focussed library of around 3,00,000 compounds was screened. Compounds with a phase screen score >2.40 were selected for docking studies. The activity of the selected hits was predicted employing the developed 3D QSAR model. Finally, three compounds were taken up for the MD simulation studies which also suggest that the identified hits might form a stable complex with hCA VII enzyme. A comparative docking study was also done with other hCA isoforms like I, II, IV, IX, and XII to examine the selectivity of the identified hits towards hCA VII. Based on these studies, three hits have been identified as potential hCA VII inhibitor which is drug-like molecules. Further, in vitro studies are required to develop leads from these identified hits.Communicated by Ramaswamy H. Sarma.

Pharmacophore-guided fragment-based design of novel mammalian target of rapamycin inhibitors: extra precision docking, fingerprint-based 2D and atom-based 3D-QSAR modelling.

Rapamycin and their derivatives known as rapalogs were the first-generation mTOR inhibitors which interacted with mTORC1 but not with the mTORC2 protein. Second-generation inhibitors could bind with both and showed excellent anti-proliferative activity. Our aim was to design novel mTOR inhibitors which could bind at both the allosteric and the kinase site. The FRB domain is present in both the mTORC1 and mTORC2 protein complexes. We have employed e-pharmacophore-guided fragment-based design to develop novel mTOR inhibitors. The affinity of designed molecules at both the sites was analysed using molecular docking in extra precision mode. The atom-based 3D-QSAR model was developed to predict the activity while the fingerprint-based 2D-QSAR model was employed to refine an identified hit as potent dual mTOR inhibitor. Ligand ASK23 showed a docking score of -15.452 kcal/mol at the allosteric site (PDB ID 5GPG) while ASK38 showed a docking score of -11.535 kcal/mol at the kinase site (PDB ID 4JT6). Ligand ASK12 showed binding energy of -106.23 kcal/mol at the allosteric site. Refined molecule ASK12a from ASK12 showed the highest predicted activity (pIC50: 6.512). The stability of the best hits and receptor complex was analysed using molecular dynamics simulation studies. Herein we report five potential mTOR dual inhibitors based on the predicted activity, drug-likeness analysis and off-target effects. To the best of our knowledge, this is the first report on pharmacophore-guided fragment-based drug design for mTOR inhibitors. This design strategy can be used for the rational drug design against other proteins for which only apo-structures are available. Communicated by Ramaswamy H. Sarma.