An insight from computational approach to explore novel, high-affinity phosphodiesterase 10A inhibitors for neurological disorders

The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A emerges as a relevant pharmacological drug target for neurological conditions such as psychosis, schizophrenia, Parkinson's, Huntington’s disease, and other memory-related disorders. In the current study, we subjected a set of 1,2,3-triazoles to be explored as PDE10A inhibitors using diverse computational approaches, including molecular docking, classical molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, steered MD, and umbrella sampling simulations. Molecular docking of cocrystallized ligands papaverine and PFJ, along with a set of in-house synthesized molecules, suggested that molecule 3i haded the highest binding affinity, followed by 3h and 3j. Furthermore, the structural stability studies using MD and MM-PBSA indicated that the 3h and 3j formed stable complexes with PDE10A. The binding free energy of −240.642 kJ/mol and −201.406 kJ/mol was observed for 3h and 3j, respectively. However, the cocrystallized ligands papaverine and PFJ exhibited comparitively higher binding free energy values of −202.030 kJ/mol and −138.764 kJ/mol, respectively. Additionally, steered MD and umbrella sampling simulations provided conclusive evidence that the molecules 3h and 3j could be exploited as promising candidates to target PDE10A. Communicated by Ramaswamy H. Sarma</p

Host–Guest Complexes of Pentiptycene Receptors Display Edge-to-Face Interaction

The pentiptycene receptors form edge-to-face complexes with a variety of aromatic guests including nitroaromatics. X-ray diffractometry revealed that compounds <b>1</b>, <b>2</b>, and <b>3</b> form host–guest assemblies with a thienyl fragment (from a neightboring molecule of <b>1</b>), benzene and nitrobenzene, respectively. X-ray studies of the three crystal structures reported here strongly suggest the edge-to-face to be a predominant binding mode between the aromatic guests and electron-rich faces of the pentiptycene aromatic cavity

Synthesis of diverse <b>β</b>-(nitrooxy)-substituted amines by regioselective ring-opening of aziridines under neat conditions

<p>An efficient and regioselective method was developed for the synthesis of β-(nitrooxy)-substituted amine derivatives by ring-opening of different aziridines with Zn(NO₃)₂·6H₂O without using additives or catalyst. A library of β-(nitrooxy)-substituted amine derivatives having a variety of substituents has been synthesized. Excellent regioselectivity, high yields, clean reaction, ease of product isolation, easily accessible reactants, and solvent-free as well as environment friendly reaction conditions are the notable advantages of the present methodology. The nitrooxy derivative was successfully transformed into hydroxy derivative by simple reduction. Gram-scale synthesis demonstrates the potential applications of the present method.</p

New Degradable Semiconducting Polymers for Photoacoustic Imaging of λ‑Carrageenan-Induced Arthritis Mouse Model

Semiconducting polymer has a high extinction coefficient and a long band absorption and can be used as a photoacoustic imaging contrast agent. However, nonbiodegradable semiconducting polymers may cause biosafety issues due to being retained in the body. Therefore, developing degradable semiconducting polymers is necessary for in vivo imaging. Herein, we developed three degradable semiconducting polymers with unique optical properties. We adjusted the optical properties of semiconducting polymers by designing the molecular structure of semiconducting polymers. Polymers with a donor−π–acceptor structure could easily improve the optical properties through adjusting the donor or acceptor units. Through adjusting the electron-donor and -acceptor units, three diketopyrrolopyrrole derivative polymers (DPPTz, DPPQu, and DPPWu) were synthesized and converted into nanosize particles. By introducing the degradable chemical groups in the main chain structure of semiconducting polymers, diketopyrrolopyrrole polymers could be degraded by ClO–. Among these nanosize particles, DPPTz NPs and DPPQu NPs were used to achieve the in vivo photoacoustic imaging of λ-carrageenan-induced arthritis mouse model. This work provides a novel design idea for the designing of red-shifted semiconducting polymer with degradable properties

Functionalized 2-Amino-4<i>H</i>-1-Benzopyran-4-yl Phosphonate Scaffolds: Synthesis, Anticancer Evaluation and Computational Studies

Prostate, breast, and lung cancers are various human cancers that have been associated with SRC kinase mutations. Therefore, the development of potent and selective SRC kinase inhibitors is an exciting area of interest for researchers. In this study, we synthesized a series of 2-amino-4H-1-benzopyran-4-yl phosphonate derivatives through a one-pot reaction involving appropriately substituted salicylaldehydes, malononitrile, and diethyl phosphite, with meglumine as the catalyst. We conducted in vitro screening of these compounds for their anticancer activity against human prostate cancer (DU-145), breast cancer (MCF-7), and lung cancer (A549) cell lines using the MTT assay. Notably, compounds 4a, 4j, 4k, and 4l exhibited promising anticancer activity. Molecular docking studies of these compounds supported their potential as therapeutic agents for SRC kinase inhibition. Specifically, compounds 4a, 4b, 4c, 4d, and 4e demonstrated strong ΔG binding affinities ranging from −7.9 to −7.4 kcal/mol. These findings suggest that these molecules hold promise for cancer treatment.</p