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Hot melt extrusion (HME) is frequently used for amorphous solid dispersion preparation and subsequent solubility and bioavailability improvement of poorly water-soluble drugs. This technique can generate numerous structures, including granules, pallets, and filaments, according to the requirement. The present study investigates the fundamental factors affecting the properties of etoricoxib-Soluplus filaments prepared by the HME method for additive manufacturing applications. The theoretical and experimental understanding of the drug–polymer miscibility was evaluated initially. Further, a detailed investigation was done to understand the role of process and formulation variables on the quality and performance of the extruded filaments. Characterization of filaments was done by Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and differential scanning calorimetry (DSC). The mechanical properties and ductility of the filaments were evaluated by texture analysis, tensile strength, and X-ray micro-computed tomography (μCT). The in vitro drug release study was performed to understand the release characteristics of the filaments. Further, the filaments were subjected to the feedability and printability study, which showed promising filament characteristics suitable for printing by the fused deposition modeling (FDM) technique. In a broader sense, such HME-based filaments, which are mostly amorphous solid dispersion in nature, can readily be used as printing ink for instant printing of personalized medicines of those drugs, which can withstand the conditions of hot melt extrusion, and FDM-based three-dimensional (3D) printing. Thus, the etoricoxib filament preparation method reported herein can be a promising approach for 3D printing applications and etoricoxib personalized therapy.

DNA–protein interactions are ubiquitous in cellular processes. Impeding unwanted nucleic acid interactions and protein recognition have therapeutic implications. Therefore, new chemical scaffolds and studies related to their structural basis of nucleic acid recognition are essential for developing high-affinity DNA binders. In this study, we have employed a fragment-based strategy to design and synthesize benzimidazole–guanidinium hybrid compounds and study the individual fragment’s role in imparting selectivity and specificity in DNA recognition. The fragments were extensively studied using thermal denaturation, circular dichroism, UV–vis absorption spectroscopy, and molecular docking techniques. The results indicate an interdependent role of the benzimidazole core, polar ends, and the DNA composition in imparting sequence-selective binding of the benzimidazole–guanidinium hybrid compounds in the DNA minor groove. Circular dichroism and molecular docking studies indicated minor groove binding analogous to classical minor groove binders such as DAPI and Hoechst 33258. Thermal denaturation studies indicated that the best binder (compound 8) gave similar thermal stabilization to B-DNA as given by DAPI.

The development of new fluorescent molecules for the recognition of specific G-quadruplex DNA structures has attracted wide attention due to their diverse roles in drug design, sensing, and cellular probing. In this work, we report the discovery of a red-emissive styryl quinolinium-based molecular rotor (compound 1), which recognizes human telomeric G-quadruplex with a distinct preference over DNA duplexes. Optical spectroscopy (UV–vis and circular dichroism)-based experiments indicated discernible interaction of compound 1with the human telomeric DNA G-quadruplex with features of stacking interactions. Fluorescence-based Job's plot revealed a 1:1 binding stoichiometry between compound 1and the human telomeric DNA G-quadruplex, and subsequent titration experiments showed micromolar affinities (Ka= 0.51 × 106M–1). Molecular docking experiments showed interactions of compound 1in the grooves of the quadruplex. Finally, we provide the application of compound 1as a reporter molecule in the fluorescence displacement experiments, which showed its ability to act as a fluorescent probe compatible with ligands having aromatic cores.

AbstractGlucagon-like peptide-1 (GLP-1) is involved in glucose-stimulated insulin secretion and weight regulating actions through the activation of the GLP-1 receptor (GLP-1R). Clinical effectiveness of GLP-1 mimetics is effective in improving glucose control in patients. Thus, identifying and developing orally active small-molecule agonists are highly desirable. This study summarizes the structure-function relationship of hGLP-1R through computational approaches and search of small molecule GLP-1R agonists. We carried out mutation guided data-driven study, for developing the GLP-1R model to explore and validate the putative site for quinoxaline analogues. The developed GLP-1R homology model was subjected to 500 ns MD simulation for validation. Various snapshots were considered to identify the best structure of GLP-1R based on correlation between experimental pEC50and various theoretical parameters (docking score, MM-GBSA ΔG bind, WM/MM ΔG bind). The putative binding site (Sitemap and WaterMap has been predicted and it matched well with the available data. Excellent correlation (R2=0.94), between pEC50 and WM/MM ΔG bind for the snapshot at 350 ns was observed after including induced-fit docking results of the most potent molecule. Enrichment calculation indicates better AUC (=0.75) for predicted complex structure. A comparison of the developed GLP-1R model with the available crystal structure shows excellent similarities and it was used for virtual screening to find small molecule agonists. The good correlation of our model with crystal structures of GLP-1R may help to understand the structure-function relationship of other secretin families.

Tuberculosis is a contagious disease that ranks among the top ten killers of humans worldwide. Mycobacterium tuberculosisis an etiological agent of tuberculosis. The prognosis of tuberculosis in patients with autoimmune diseases is high due to treatment with anti-TNF-alpha therapy.

AbstractOsteoarthritis (OA) is the most common form of arthritis with no available disease-modifying treatments, and is a major cause of disability. Matrix metalloproteinase 13 (MMP-13) is vital for OA progression and thus, inhibition of MMP-13 is an effective strategy to treat OA. Since the past few decades, drug repurposing has gained substantial popularity worldwide as a time- and cost-effective approach to find new indications for the existing drugs. Therefore, more than 40 X-ray co-crystal structures of the human MMP-13 with bound inhibitors are investigated to gain the structural insights such as conserved direct interactions with binding site residues, namely Ala-238, Thr-245 and Thr-247. Afterwards, enrichment study using active and decoy set of ligands revealed three MMP-13 structures (PDB-IDs: 1XUC, 3WV1 and 5BPA) with optimal enrichment performance. Docking-based screening of existing drugs against the three crystal structures followed by binding free-energy calculation suggested drugs namely eltrombopag, cilostazol and domperidone as potential MMP-13 inhibitors that need further experimental validation. These insights may serve as a potential starting point of further experimental validation and structure-based drug design/repurposing of MMP-13 inhibitors for the treatment of OA.Abbreviations2Dtwo-dimensional3Dthree-dimensionalFDAFood and Drug AdministrationMM-GBSAMolecular Mechanics Generalized Born Surface AreaMMPsmatrix metalloproteinasesMMP-13matrix metalloproteinase 13NMRnuclear magnetic resonanceOAosteoarthritisPDBProtein Data BankPDB-IDProtein Data Bank IDPLIPprotein–ligand interaction profilerROCreceiver operating characteristic,RMSDroot mean square deviationCommunicated by Ramaswamy H. Sarma

AbstractWe report herein detailed structural insights into the ligand recognition modes guiding bromodomain selectivity, enrichment analysis and docking-based database screening for the identification of the FDA-approved drugs that have potential to be the human BRD4 inhibitors. Analysis of multiple X-ray structures prevailed that the lysine-recognition sites are highly conserved, and apparently, the dynamic ZA loop guides the specific ligand-recognition. The protein–ligand interaction profiling revealed that both BRD2 and BRD4 shared hydrophobic interaction of bound ligands with PRO-98/PRO-82, PHE-99/PHE-83, LEU-108/LEU-92 and direct H-bonding with ASN-156/ASN-140 (BRD2/BRD4), while on the other hand the water-mediated H-bonding of bound ligands with PRO-82, GLN-85, PRO-86, VAL-87, ASP-88, LEU-92, TYR-97 and MET-132, and aromatic π–π stacking with TRP-81 prevailed as unique interaction in BRD4, and were not observed in BRD2. Subsequently, through ROC curve analysis, the best enrichment was found with PDB-ID 4QZS of BRD4 structures. Finally, through docking-based database screening study, we found that several drugs have better binding affinity than the control candidate lead (+)-JQ1 (Binding affinity = -7.9 kcal/mol), a well-known BRD4 inhibitor. Among the top-ranked drugs, azelastine, a selective histamine H1 receptor antagonist, showed the best binding affinity of –9.3 kcal/mol and showed interactions with several key residues of the acetyl lysine binding pocket. Azelastine may serve as a promising template for further medicinal chemistry. These insights may serve as basis for structure-based drug design, drug repurposing and the discovery of novel BRD4 inhibitors.Communicated by Ramaswamy H. Sarma