Predicting the conformational flexibility of antibody and T cell receptor complementarity-determining regions

Many proteins are highly flexible and their ability to adapt their shape can be fundamental to their functional properties. For example, the flexibility of antibody complementarity-determining region (CDR) loops influences binding affinity and specificity, making it a key factor in understanding and designing antigen interactions. With methods such as AlphaFold, it is possible to computationally predict a single, static protein structure with high accuracy. However, the reliable prediction of structural flexibility has not yet been achieved. A major factor limiting such predictions is the scarcity of suitable training data. Here we focus on predicting the structural flexibility of functionally important antibody and T cell receptor CDR3 loops. To this end, we constructed ALL-conformations by extracting CDR3s and CDR3-like loop motifs from all structures deposited in the Protein Data Bank. This dataset comprises 1.2 million loop structures representing more than 100,000 unique sequences and captures all experimentally observed conformations of these motifs. Using this dataset, we develop ITsFlexible, a deep learning tool with graph neural network architecture. We trained the model to binary classify CDR loops as ‘rigid’ or ‘flexible’ from inputs of antibody structures. ITsFlexible outperforms all alternative approaches on our crystal structure datasets and successfully generalizes to molecular dynamics simulations. We also used ITsFlexible to predict the flexibility of three CDRH3 loops with no solved structures and experimentally determined their conformations using cryogenic electron microscopy

Metronomic Docetaxel in PRINT Nanoparticles and EZH2 Silencing Have Synergistic Antitumor Effect in Ovarian Cancer

The purpose of this study was to investigate the antitumor effects of a combination of metronomic doses of a novel delivery vehicle, PLGA-PRINT nanoparticles containing docetaxel, and anti-angiogenic mEZH2 siRNA incorporated into chitosan nanoparticles. In vivo dose-finding studies and therapeutic experiments were conducted in well-established orthotopic mouse models of epithelial ovarian cancer. Antitumor effects were determined on the basis of reduction in mean tumor weight and number of metastatic tumor nodules in the animals. The tumor tissues from these in vivo studies were stained to evaluate the proliferation index (Ki67), apoptosis index (cleaved caspase 3), and microvessel density (CD31). The lowest dose of metronomic regimen (0.5 mg/kg) resulted in significant reduction in tumor growth. The combination of PLGA-PRINT-docetaxel and CH-mEZH2 siRNA showed significant antitumor effects in the HeyA8 and SKOV3ip1 tumor models (p<0.05). Individual as well as combination therapies showed significant anti-angiogenic, anti-proliferative, and pro-apoptotic effects, and combination therapy had additive effects. Metronomic delivery of PLGA-PRINT-docetaxel combined with CH-mEZH2 siRNA has significant antitumor activity in preclinical models of ovarian cancer

Assessment of age-related changes in pediatric gastrointestinal solubility

PurposeCompound solubility serves as a surrogate indicator of oral biopharmaceutical performance. Between infancy and adulthood, marked compositional changes in gastrointestinal (GI) fluids occur. This study serves to assess how developmental changes in GI fluid composition affects compound solubility.MethodsSolubility assessments were conducted in vitro using biorelevant media reflective of age-specific pediatric cohorts (i.e., neonates and infants). Previously published adult media (i.e., FaSSGF, FeSSGF, FaSSIF.v2, and FeSSIF.v2) were employed as references for pediatric media development. Investigations assessing age-specific changes in GI fluid parameters (i.e., pepsin, bile acids, pH, osmolality, etc.) were collected from the literature and served to define the composition of neonatal and infant media. Solubility assessments at 37°C were conducted for seven BCS Class II compounds within the developed pediatric and reference adult media.ResultsFor six of the seven compounds investigated, solubility fell outside an 80–125% range from adult values in at least one of the developed pediatric media. This result indicates a potential for age-related alterations in oral drug performance, especially for compounds whose absorption is delimited by solubility (i.e., BCS Class II).ConclusionDevelopmental changes in GI fluid composition can result in relevant discrepancies in luminal compound solubility between children and adults.<br/

The Subodhini : being a commentary by Bhaṭṭa Viśveśvara on the Mitâkṣharâ of Śrĩ Vijñâneśwara on the Yâjñavalkya-Smṛiti : Sanskrit text

application/pdfapplication/pdf1. आवृत्तिःIn Sanskrit, prefatory mattar in Englis