Identification of Potential Aldose Reductase Inhibitors Using Convolutional Neural Network-Based in Silico Screening.

Aldose reductase (ALR2) is a notable enzyme of the polyol pathway responsible for aggravating diabetic neuropathy complications. The first step begins when it catalyzes the reduction of glucose to sorbitol with NADPH as a coenzyme. Elevated concentrations of sorbitol damage the tissues, leading to complications like neuropathy. Though considerable effort has been pushed toward the successful discovery of potent inhibitors, its discovery still remains an elusive task. To this end, we present a 3D convolutional neural network (3D-CNN) based ALR2 inhibitor classification technique by dealing with snapshots of images captured from 3D chemical structures with multiple rotations as input data. The CNN-based architecture was trained on the 360 sets of image data along each axis and further prediction on the Maybridge library by each of the models. Subjecting the retrieved hits to molecular docking leads to the identification of the top 10 molecules with high binding affinity. The hits displayed a better blood-brain barrier penetration (BBB) score (90% with more than four scores) as compared to standard inhibitors (38%), reflecting the superior BBB penetrating efficiency of the hits. Followed by molecular docking, the biological evaluation spotlighted five compounds as promising ALR2 inhibitors and can be considered as a likely prospect for further structural optimization with medicinal chemistry efforts to improve their inhibition efficacy and consolidate them as new ALR2 antagonists in the future. In addition, the study also demonstrated the usefulness of scaffold analysis of the molecules as a method for investigating the significance of structurally diverse compounds in data-driven studies. For reproducibility and accessibility purposes, all of the source codes used in our study are publicly available.

Novel indole retinoid derivative induces apoptosis and cell cycle arrest and modulates AKT and ERK signaling in HL-60 cells.

Chemotherapy with targeted drugs is the first line therapy option for acute and chronic myeloid leukemia. However, hematopoietic stem cell transplantation may be used in high-risk patients or patients with failed responses to chemo drugs. Discovery and development of more effective new agents with lower side effects is the main aim of leukemia treatment. In this study, a novel retinoid compound with tetrahydronaphthalene ring was synthesized and evaluated for anticancer activity in human chronic and acute myeloid leukemia cell lines K562 and HL-60. Novel N-(1H-indol-1-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide was synthesized based on molecular hybridization of the two different bioactive structures retinoid head and indole. The effects of the synthesized carboxamide compound, which was referred to as compound 5, were determined in K562 chronic myeloid leukemia and HL-60 acute myeloid leukemia cell lines and L929 fibroblast cell line, which served as a control. Colorimetric MTT and caspase3 activity tests, flow cytometry, western blot, and microscopic examinations were used to evaluate biological activity. Compound 5 more effectively induced cell death in HL60 cells in comparison to K562 cells and L929 fibroblast cells. Therefore, further mechanism of cell death was investigated in HL60 cell line. It was found that compound 5 induced remarkable cytotoxicity, caspase3 activation, and PARP fragmentation in HL60 cells. Flow cytometric staining showed that the percentage of cells arrested in G0/G1 was also increased with compound 5 treatment. Important modulator proteins of cell proliferation p-ERK, p-AKT, and p-m-TOR were also found to be inhibited with compound 5 treatment. Collectively, our results reveal compound 5, which is a novel indole retinoid compound as a potential active agent for the treatment of acute promyelocytic leukemia.

Synthesis of Some Benzimidazole-derived Molecules and their Effects on PARP-1 Activity and MDA-MB-231, MDA-MB-436, MDA-MB-468 Breast Cancer Cell Viability.

BACKGROUND: Poly (ADP-ribosyl) polymerase-1 (PARP-1) inhibitors are compounds that are used to treat cancers, which are defective in DNA-repair and DNA Damage-Response (DDR) pathways. OBJECTIVE: In this study, a series of potential PARP-1 inhibitor substituted (piperazine-1-carbonyl)phenyl)-1Hbenzo[ d]imidazole-4-carboxamide compounds were synthesised and tested for their PARP-1 inhibitory and anticancer activities. METHODS: Compounds were tested by cell-free colorimetric PARP-1 activity and MTT assay in MDA-MB-231, MDA-MB-436, MDA-MB-468 breast cancer, and L929 fibroblast cell lines. RESULTS: Our results showed that compound 6a inhibited viability in MDA-MB-231 and MDA-MB-468 cells whereas 8a inhibited viability in MDA-MB-468 cells. Compound 6b significantly inhibited cell viability in tested cancer cells. However, 6b exhibited toxicity in L929 cells, whereas 6a and 8a were found to be non-toxic for L929 cells. Compounds 6a, 6b and 8a exhibited significant inhibition of PARP-1 activity. CONCLUSION: These three compounds exhibited PARP-1 inhibitory activities and anticancer effects on breast cancer cells, and further research will enlighten the underlying mechanisms of their effects.

Three-Dimensional Analysis of Binding Sites for Predicting Binding Affinities in Drug Design.

Understanding the interaction between drug molecules and proteins is one of the main challenges in drug design. Several tools have been developed recently to decrease the complexity of the process. Artificial intelligence and machine learning methods offer promising results in predicting the binding affinities. It becomes possible to do accurate predictions by using the known protein-ligand interactions. In this study, the electrostatic potential values extracted from 3-dimensional grid cubes of the drug-protein binding sites are used for predicting binding affinities of related complexes. A new algorithm with a dynamic feature selection method was implemented, which is derived from Compressed Images For Affinity Prediction (CIFAP) study, to predict binding affinities of Checkpoint Kinase 1 and Caspase 3 inhibitors.

Apoptotic Effects of Some Tetrahydronaphthalene Derivatives on K562 Human Chronic Myelogenous Leukemia Cell Line.

BACKGROUND: Retinoids which are vitamin A (Retinol) derivatives have been suggested to mediate the inhibition of cancer cell growth and apoptosis. It has been reported that all trans retinoic acid (ATRA) exhibited suppressive effects on different types of leukemia including chronic myelogenous leukemia. OBJECTIVE: In the present study, we aim to find out the effects of 6 synthetic N-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalene-2-yl)-carboxamide derivatives (compound 6-12) on cell viability and apoptotic pathways in K562 human chronic myelogenous leukemia cell line. METHODS: Cell viability and apoptosis were examined by spectrophotometric thiazolyl blue tetrazolium bromide (MTT) and caspase-3 assay, western blot, RT-PCR and flow cytometry. RESULTS: Our results indicated that compound 6 (5-(1,2-Dithiolan-3-yl)-N-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)pentanamide), 8 (4-(3,4-Dimethoxyphenyl)-N-(3,5,5,8,8-pentamethyl-5,6,7,8- tetrahydronaphthalen-2-yl)butanamide) and 11 (E-3-(4-Hydroxy-3-methoxyphenyl)-N-(3,5,5,8,8-pentamethyl- 5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide) exhibited apoptotic effects in K562 human chronic myelogenous leukemia cell line and induced caspase 3, PARP cleavage, Bax/Bcl-2 ratio, Bad and Bim gene expressions. CONCLUSION: Some retinoid derivatives tested in this study induced apoptosis of K562 cells which suggest that these compounds may serve as potential agents in the treatment of chronic myelogenous leukemia.

An application of CIFAP for predicting the binding affinity of Chk1 inhibitors derived from 2-aminothiazole-4-carboxamide.

Investigation of protein-ligand interactions obtained from experiments has a crucial part in the design of newly discovered and effective drugs. Analyzing the data extracted from known interactions could help scientists to predict the binding affinities of promising ligands before conducting experiments. The objective of this study is to advance the CIFAP (compressed images for affinity prediction) method, which is relevant to a protein-ligand model, identifying 2D electrostatic potential images by separating the binding site of protein-ligand complexes and using the images for predicting the computational affinity information represented by pIC50 values. The CIFAP method has 2 phases, namely, data modeling and prediction. In data modeling phase, the separated 3D structure of the binding pocket with the ligand inside is fitted into an electrostatic potential grid box, which is then compressed through 3 orthogonal directions into three 2D images for each protein-ligand complex. Sequential floating forward selection technique is performed for acquiring prediction patterns from the images. In the prediction phase, support vector regression (SVR) and partial least squares regression are used for testing the quality of the CIFAP method for predicting the binding affinity of 45 CHK1 inhibitors derived from 2-aminothiazole-4-carboxamide. The results show that the CIFAP method using both support vector regression and partial least squares regression is very effective for predicting the binding affinities of CHK1-ligand complexes with low-error values and high correlation. As a future work, the results could be improved by working on the pose of the ligands inside the grid.

Retinoid N-(1H-benzo[d]imidazol-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide induces p21-dependent senescence in breast cancer cells.

Retinoids have been implicated as pharmacological agents for the prevention and treatment of various types of cancers, including breast cancers. We analyzed 27 newly synthesized retinoids for their bioactivity on breast, liver, and colon cancer cells. Majority of the retinoids demonstrated selective bioactivity on breast cancer cells. Retinoid 17 had a significant inhibitory activity (IC50 3.5 µM) only on breast cancer cells while no growth inhibition observed with liver and colon cancer cells. The breast cancer selective growth inhibitory action by retinoid 17 was defined as p21-dependent cell death, reminiscent of senescence, which is an indicator of targeted receptor mediated bioactivity. A comparative analysis of retinoid receptor gene expression levels in different breast cancer cells and IC50 values of 17 indicated the involvement of Retinoid X receptors in the cytotoxic bioactivity of retinoid 17 in the senescence associated cell death. Furthermore, siRNA knockdown studies with RXRγ induced decrease in cell proliferation. Therefore, we suggest that retinoid derivatives that target RXRγ, can be considered for breast cancer therapies.

Inhibitory effects of indole α-lipoic acid derivatives on nitric oxide production in LPS/IFNγ activated RAW 264.7 macrophages.

Alpha-lipoic acid (α-lipoic acid) is a potent antioxidant compound that has been shown to possess anti-inflammatory effects. RAW 264.7 macrophages produce various inflammatory mediators such as nitric oxide, IL-1ß, IL-6 and TNF-alpha upon activation with LPS (Lipopolysaccharide) and IFNγ (interferon gamma). In this study, the effect of 12 synthetic indole α-lipoic acid derivatives on nitric oxide production and iNOS (inducible nitric oxide synthase) protein expression in LPS/IFNγ activated RAW 264.7 macrophages was determined. Cell proliferation, nitric oxide levels and iNOS protein expression were examined with thiazolyl blue tetrazolium blue test, griess assay and western blot, respectively. Our results showed that all of the indole α-lipoic acid derivatives showed significant inhibitory effects on nitric oxide production and iNOS protein levels (p < 0.05). The most active compounds were identified as compound I-4b, I-4e and II-3b. In conclusion, these indole α-lipoic acid derivatives may have the potential for treatment of inflammatory conditions related with high nitric oxide production.

Compressed images for affinity prediction-2 (CIFAP-2): an improved machine learning methodology on protein-ligand interactions based on a study on caspase 3 inhibitors.

The aim of this study is to propose an improved computational methodology, which is called Compressed Images for Affinity Prediction-2 (CIFAP-2) to predict binding affinities of structurally related protein-ligand complexes. CIFAP-2 method is established based on a protein-ligand model from which computational affinity information is obtained by utilizing 2D electrostatic potential images determined for the binding site of protein-ligand complexes. The quality of the prediction of the CIFAP-2 algorithm was tested using partial least squares regression (PLSR) as well as support vector regression (SVR) and adaptive neuro-fuzzy inference system (ANFIS), which are highly promising prediction methods in drug design. CIFAP-2 was applied on a protein-ligand complex system involving Caspase 3 (CASP3) and its 35 inhibitors possessing a common isatin sulfonamide pharmacophore. As a result, PLSR affinity prediction for the CASP3-ligand complexes gave rise to the most consistent information with reported empirical binding affinities (pIC(50)) of the CASP3 inhibitors.

Synthesis, anticancer activities and molecular modeling studies of novel indole retinoid derivatives.

In this study, novel (E)-3-(5-substituted-1H-indol-3-yl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (5(a-e)) derivatives were synthesized and their anticancer effects were determined in vitro. Novel indole retinoid compounds except 5e have anti-proliferative capacity in liver, breast and colon cancer cell lines. This anti-proliferative effect was further analyzed in breast cancer cell line panel by using the most potent compound 5a. It was determined that 5a can inhibit proliferation at very low IC(50) concentrations in all of the breast cancer cell lines. Here, we present some evidence on apoptotic termination of cancer cell proliferation which may be primarily driven by the inhibition of RXRα and, to a lesser extent, RXRγ.

Synthesis and effects of some novel tetrahydronaphthalene derivatives on proliferation and nitric oxide production in lipopolysaccharide activated Raw 264.7 macrophages.

In this study, novel N-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-carboxamide (6-15) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (16-32) derivatives were synthesized and their in vitro effects at 5 µM and 50 µM concentrations on proliferation and nitric oxide (NO*) production in lipopolysaccharide (LPS) activated RAW 264.7 macrophage cells were determined. Compounds 12, 17, 24 and 26 were found to decrease nitrite levels in a dose-dependent manner in LPS-activated cells. At the tested concentrations, these compounds did not exhibit cytotoxic effects. Interestingly, compound 27 which contains nitroxide free radical was the most active compound in this series showing 59.2% nitrite inhibition in LPS-activated macrophage cells.

Adaptive neuro-fuzzy inference system (ANFIS): a new approach to predictive modeling in QSAR applications: a study of neuro-fuzzy modeling of PCP-based NMDA receptor antagonists.

This paper proposes a new method, Adaptive Neuro-Fuzzy Inference System (ANFIS) to evaluate physicochemical descriptors of certain chemical compounds for their appropriate biological activities in terms of QSAR models with the aid of artificial neural network (ANN) approach combined with the principle of fuzzy logic. The ANFIS was utilized to predict NMDA (N-methyl-d-Aspartate) receptor binding activities of phencyclidine (PCP) derivatives. A data set of 38 drug-like compounds was coded with 1244 calculated molecular structure descriptors (clustered in 20 data sets) which were obtained from several sources, mainly from Dragon software. Prior to the progress to the ANFIS system, descriptors from the best subsets were selected using unsupervised forward selection (UFS) to eliminate redundancy and multicollinearity followed by fuzzy linear regression algorithm (FLR) which was used for variable selection. ANFIS was applied to train the final descriptors (Mor22m, E3s, R3v+, and R1e+) using a hybrid algorithm consisting of back-propagation and least-square estimation while the optimum number and shape of related functions were obtained through the subtractive clustering algorithm. Comparison of the proposed method with traditional methods, that is, multiple linear regression (MLR) and partial least-square (PLS) was also studied and the results indicated that the ANFIS model obtained from data sets achieved satisfactory accuracy.

Antimicrobial activities of some tetrahydronaphthalene-benzimidazole derivatives.

Novel retinoid derivatives containing a benzimidazole moiety were synthesized and tested for their antimicrobial activity. Their antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Candida krusei and Candida albicans were evaluated. While some of the compounds exhibited moderate activity against MRSA, S. aureus, E. faecalis, C. krusei and C. albicans, none of the compounds showed activity against E. coli and P. aeruginosa.

Synthesis and evaluation of in vitro antioxidant capacities of some benzimidazole derivatives.

New, except 1d, melatonin analogue benzimidazole derivatives were synthesized and characterized in the present study. The potential role of melatonin as an antioxidant by scavenging and detoxifying ROS raised the possibility that compounds that are analogous to melatonin can also be used for their antioxidant properties. Therefore the antioxidant effects of the newly synthesized compounds were investigated in vitro by means of their inhibitory effect on hydrogen peroxide-induced erythrocyte membrane lipid peroxidation (EMLP) and on various erythrocyte antioxidant enzymes viz. superoxide dismutase (SOD), catalase (CAT) and glucose-6-phosphate dehydrogenase (G6PD). The synthesized benzimidazole derivatives showed remarkable antioxidant activity in vitro in the H2O2-induced EMLP system. Furthermore their effects on various antioxidant enzymes are discussed and evaluated from the perspective of structure- activity relationships.

Synthesis and antioxidant activity of new tetrahydro-naphthalene-indole derivatives as retinoid and melatonin analogs.

A number of retinoid-related compounds represent classes of antioxidative and proapoptotic agents with promising potential in the treatment of neoplastic diseases. Indeed, the synthetic retinoid amide fenretinide [N-(4-hydroxyphenyl)retinamide] induces apoptosis of cancer cells and acts as a chemotherapeutic drug in cancer therapy. In the present work, and as a continuation of our studies on retinoid-type compounds, the synthesis of melatonin retinamide derivatives was studied as a novel series of melatonin retinoids, using the condensation reaction sequence involving tetrahydrotetramethylnaphthalene carboxylic acid and appropriate melatonin-type moieties. Despite of the weak DPPH inhibition activity pattern of the synthesized compounds, some of them showed a strong inhibition on lipid peroxidation (IVa-b, Va, and VIIa-c, 88, 96, 90, 94, 93, and 86%, respectively at 10(-4) M concentration) when melatonin (85% at 10(-4) M concentration) was used as a reference compound.

Synthesis and potent antimicrobial activities of some novel retinoidal monocationic benzimidazoles.

Several 2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-benzimidazole-5-carboxamidine analogues were synthesized for their antibacterial and antifungal activities against S. aureus, Methicillin-resistant S. aureus (MRSA), C. albicans, and C. krusei. MIC values of the targeted compounds 43-58 are comparable to those of Fluconazole and Sultamicillin. The most potent compounds, 51 and 53, showed MIC values as 0.78 and 1.56 microg/mL against S. aureus and C. albicans, respectively.

Syntheses of novel indole lipoic acid derivatives and their antioxidant effects on lipid peroxidation.

The aim of the study was to examine antioxidant properties of conjugates based on indole and lipoic acid moieties. The design and syntheses of novel indole alpha-lipoic acid derivatives were performed. The antioxidant properties of target compounds were investigated using rat liver microsomal, NADPH-dependent lipid peroxidation inhibition. Some of the target compounds, especially those containing amide linker at position 5 of indole ring, proved to be highly effective in inhibiting lipid peroxidation as compared to alpha-lipoic acid.

Antioxidant properties of novel benzimidazole retinoids.

Our approach was to examine the antioxidant activity of novel retinoid derivatives containing the benzimidazole moiety. Their in vitro effects on rat liver microasomal, NADPH-dependent lipid peroxidation levels and superoxide anion formation were determined. Lipid peroxidation in rat liver microsomes was reduced by some of the compounds in a dose-dependent manner.

Recent studies of aldose reductase enzyme inhibition for diabetic complications.

Aldose reductase [ALR2; EC 1.1.1.21], a key enzyme of polyol pathway, catalyzes NADPH-dependent reduction of glucose to sorbitol (Sorbitol pathway), and an excessive accumulation of intracellular sorbitol found in various tissues of diabetic animals and in cells cultured under high glucose conditions has been proposed to be an important factor for the pathogenesis of diabetic complications. The only strategy shown to be consistently beneficial in the treatment of diabetic complications is meticulous control of blood glucose. However, aldose reductase (AR) enzyme inhibition is becoming one of the therapeutic strategies that have been proposed to prevent or ameliorate long-term diabetic complications. Therefore, AR inhibitors (ARIs) hold promise for reducing metabolic nerve injury, but further study is needed. On the other hand, there is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. This relationship between diabetic complications and free radical production was also under investigation. The studies suggest that hydroxyl radical is indirectly inhibited by ARIs resulting from decreasing polyol levels and hydroxyl radical formation is related to the early stages of diabetic complications, possibly via the Fenton reaction involving H(2)O(2) produced from the activated polyol pathway. Therefore, it is proposed that hydroxyl radical may accelerate damage to the cell membranes resulting from polyol accumulation. The search for specific inhibitors of AR enzyme has still become a major pharmaceutic challenge, though a number of AR inhibitors have so far been assessed for diabetic complications.