Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2–AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID?=?3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2–AGR2 homodimer inhibitors having FRED score lower than ? 7.8 kcal/mol in which the top 5 drugs’ binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2–AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation.

Graphic abstract

A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2–AGR2 homodimer.

     

Optimizing nozzle convergent angle using central composite design on the particle velocity and acoustic power level for single-hose dry ice blasting nozzle

Journal of Thermal Analysis and Calorimetry - One of the important parameters in developing dry ice blasting nozzle is the high-speed dry ice pellets. However, many studies focus primarily only on...     

Weighted ebyev-Ostrowski type inequalities

In account of the famous ebyev inequality,a rich theory has appeared in the literature.We establish some new weighted ebyev type integral inequalitíes.Our proofs are of independent interest and provide new estimates on these types of inequalities.     

Alternate technique for simultaneous measurement of photoionization cross-section of isotopes by TOF mass spectrometer

New measurements of photoionization cross-sections of the lithium isotopes are reported employing a Time of Flight (TOF) mass spectrometer in conjunction with an atomic beam apparatus. Using a two-step selective photoionization and saturation technique, we have simultaneously measured the photoionization cross-section of the 2p excited state of both the isotopes Li⁶ and Li⁷ as 15±2.5 Mb and 18 ±2.5 Mb where as the corresponding number densities have been determined as N₀≈5.3×10¹⁰ atoms/cm³ and N₀≈6.2×10¹¹ atoms/cm³ respectively.     

Synthesis and spectral characterization of some new N-substituted 2-aminobenzothiazoles, 2-aminothiazolopyridines and 2-aminothiazoloquinolines

A series of N-substituted 2-aminobenzothiazoles, 2-aminothiazolopyridines, and 2-aminothiazoloquinolines were prepared by the cyclization of N,N'-disubstituted thiourea derivatives by bromine in acetic acid. The uv, ir and nmr data for these compounds are presented and discussed.     

DFT study of the infrared and Raman spectra of photochromic Fulgide; 3-Dicyclopropylmethylene-4-E-[1-(2,5-dimethyl-3-furyl)ethylidene]-5-(4-nitrophenylcyanomethylenetetrahydrofuran-2-one

The present work reports a theoretical study of vibrational signatures of the photochromic molecular transformation between two photochromic heterocyclic isomers. Raman and infrared (IR) spectra of the E (ring-opened form) and C (ring-closed form) photoisomers of 3-Dicyclopropylmethylene-4-E-[1-(2,5-dimethyl-3-furyl)ethylidene]-5-(4-nitrophenylcyanomethylenetetrahydrofuran-2-one have been calculated in gas phase in the region of 3500–500 cm^?1 for both molecules in their ground state. Calculations of the structure parameters and frontier molecular orbitals were carried out using ab initio electronic structure theory at the Hartree-Fock, density functional theory, and Moller-Plesset perturbation theory levels, while calculations of the IR and Raman spectra were carried out using density functional theory with B3LYP functional and 6-31+g(d,p) basis set. After comparing the predicted spectra of both E-form and C-form, we were able to probe the changes that arise upon the ring-closure/ring-opening transformation. The computational results showed that the C-form is ≈?10.7 kcal/mol lower in energy than the E-form. In addition, two different derivatives were adopted for both E-form and C-form to demonstrate the effect of substituents on the stability of the photoisomers. The theoretical predictions agree well with the reported experimental data, accounting for the molecular structure transformation of the photochromic isomers.     

DABCO–PEG ionic liquid-based synthesis of acridine analogous and its inhibitory activity on alkaline phosphatase

In world, many people struggle with viral, parasitic, bacterial, cancer, and other diseases. Therefore, numerous chemists seek to develop less toxic, more selective, and effective medicines. Most therapeutic medicines are based on inhibition of specific enzymes. Acridines are interesting heterocyclic structures that are much sought after targets attributed to their wide biological activities and feature to display potent enzymes inhibitory effects. Their approach of action is owing to DNA interaction and subsequent effects on the biological functions linked to DNA and associated enzymes. In this regards, we synthesized acridine analogous through 1,4-diazabicyclo[2.2.2]octane (DABCO)–polyethylene glycol-400 (PEG-400) mediated ionic liquid approach. DABCO–PEG-400-mediated IL was prepared through the DABCO alkylation using 1-bromopentane followed by mixing with PEG-400. The synthesized analogous were investigated as inhibitors of alkaline phosphatase, which is a nonspecific phosphomonoester hydrolase that catalyzes the hydrolysis of broad spectrum of organic monophosphates. Analogue viz. 3,3,6,6-tetramethyl-9-(4-nitrophenyl)-2,3,4,5,6,7,9,10-octahydroacridine-1,8-dione was found to be potent alkaline phosphatase inhibitor.     

Bis(ammonium) tris­(hexa­aqua­magnesium) tetra­kis(hydrogen phosphite)

The structure of the title compound, (NH₄)₂[Mg(H₂O)₆]₃(HPO₃)₄, consists of [Mg(H₂O)₆]²⁺ and (NH₄)⁺ cations and (HPO₃)²⁻ anions held together by an intricate network of hydrogen bonds involving all H atoms except for one linked directly to a P atom. The Mg²⁺ cations are octa­hedrally coordinated by six water mol­ecules. One of the Mg atoms is located on a site with 2/m symmetry, whereas the other Mg atom and the P and N atoms occupy sites with m symmetry.