Design of new CD38 inhibitors based on CoMFA modelling and molecular docking analysis of 4‑amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides

In this study, based on molecular docking analysis and comparative molecular field analysis (CoMFA) modelling of a series of 71 CD38 inhibitors including 4?amino-8-quinoline carboxamides and 2,4-diamino-8-quinazoline carboxamides, new CD38 inhibitors were designed. The interactions of the molecules with the greatest and the lowest activities with the nicotinamide mononucleotide (NMN) binding site were investigated by molecular docking analysis. A CoMFA model with four partial least squares regression (PLSR) components was developed to predict the CD38 inhibitory activity of the molecules. The r² values for the training and test sets were 0.89 and 0.82, respectively. The Q² values for leave-one-out cross-validation (LOO-CV) and leave-many-out cross-validation (LMO-CV) tests on the training set were 0.65 and 0.64, respectively. The CoMFA model was validated by calculating several statistical parameters. CoMFA contour maps were interpreted, and structural features that influence the CD38 inhibitory activity of molecules were determined. Finally, seven new CD38 inhibitors with greater activity with respect to the greatest active molecules were designed.     

The identification of new ATAD2 bromodomain inhibitors: the application of combined ligand and structure-based virtual screening

Ligand-based virtual screening (LBVS) and structure-based virtual screening (SBVS) approaches were used to identify new inhibitors for ATAD2 bromodomain. The LBVS approach was used to search 23,129,083 clean compounds to identify compounds similar to an active compound with reported pIC₅₀ equal to 7.2. Based on LBVS results, 19 compounds were selected. To perform SBVS, by applying nine filters on 23,129,083 clean compounds, 1,057,060 compounds were selected. After performing SBVS on these selected compounds with idock software, 16 compounds with the lowest binding energies were selected. More accurate molecular docking analysis was performed on these 35 selected compounds by using iGEMDOCK software and six of them with the lowest binding energies were selected as hit compounds. These compounds were zinc36647229, zinc77969074, zinc13637358, zinc77971540, zinc12991296 and zinc19374204.     

The in silico identification of potent anti-cancer agents by targeting the ATP binding site of the N-domain of HSP90

To identify new HSP90 inhibitors, the ATP binding site of the N-domain of HSP90 was targeted by molecular docking of a library of 23,129,083 compounds (from the ZINC database) to the ATP binding site of the N-domain of HSP90. Structure-based virtual screen (SBVS) was performed using idock software on the istar web platform. Based on idock binding energies, 40 molecules were considered as HSP90 inhibitors. In the next step, the 40 molecules and the compound AT13387 (Onalespib) were docked to the XJX binding site using AutoDock Vina software. By comparing the binding energies of the 40 molecules selected with compound AT13387, 26 molecules were selected. By applying the rule of five, eight molecules were selected as hit compounds. The interactions of these eight compounds with the XJX binding site were obtained and investigated, and two-dimensional interaction maps were provided for the others. Finally, computing the toxicity of these compounds with the ProTox-II webserver shows that three compounds, namely ZINC89453765, ZINC23918431 and ZINC12414793, can be considered as good HSP90 inhibitors. These compounds are inactive for nuclear receptor signalling and stress response pathways including heat shock response, so do not have the limitations of common HSP90 inhibitors. They are also inactive for hepatotoxicity, carcinogenicity, immunotoxicity, mutagenicity and cytotoxicity.     

Information Loss for QCD Matter in AdS Black Holes at LHC

In this paper, we find the information loss for QCD matter in AdS black holes at LHC by extending the Gottesman and Preskill methode to AdS black holes. We calculate the information transformation from the collapsing matter to the state of outgoing Hawking radiation for both quarks and gluons. It is noticed that for finite values of quark and gluon energies, information from all emission processes experiences some degrees of loss. Possible explanation for this feature will be presented in this paper.     

Insights into the current status of privileged N-heterocycles as antileishmanial agents

Molecular Diversity - Leishmania, one of the most important neglected tropical diseases, is endemic in several regions of the world and hence regarded as a serious threat to public health. Major...     

Fe3O4-modified graphene oxide as a sorbent for sequential magnetic solid phase extraction and dispersive liquid phase microextraction of thallium

Microchimica Acta - A combination of magnetic solid phase extraction (MSPE) and dispersive liquid phase microextraction (DLPME) was applied in a new method for preconcentration and extremely...     

Holographic cosmology from a system of M2–M5 branes

In this paper, we analyze the holographic cosmology using a M2–M5 brane configuration. In this configuration, a M2-brane will be placed in between a M5-brane and an anti-M5-brane. The M2-brane will act as a channel for energy to flow from an anti-M5-brane to a M5-brane, and this will increase the degrees of freedom on the M5-brane causing inflation. The inflation will end when the M5-brane and anti-M5-brane get separated. However, at a later stage the distance between the M5-brane and the anti-M5-bran can reduce and this will cause the formation of tachyonic states. These tachyonic states will again open a bridge between the M5-branes and the anti-M5-branes, which will cause further acceleration of the universe.