Letters in Drug Design & Discovery - Volume 17, Issue 10, 2020

Background: Obsessive-Compulsive Disorder (OCD) is considered as a serious disabling psychiatric disorder, influencing 2-3% of the total general population, with an unknown etiology. Methods: A comprehensive literature search in electronic databases was performed to investigate treatments targeting inflammation in patients suffering from OCD. Results: Recent studies display that inflammation processes and the dysfunction of the immune system are likely to play a role in the pathophysiology of OCD, indicating that the disturbances in neurotransmitters such as serotonin and dopamine cannot be alone involved in the development of OCD. Therefore, it seems that medications with anti-inflammatory effects have the potential to be evaluated as a new therapeutic strategy for OCD. However, this issue can be studied closely if OCD etiological factors are thoroughly understood. The present review study aims at gathering all obtained results concerning new treatments targeting inflammation in OCD patients. Reviewing the conducted studies shows that the use of agents with anti-inflammatory properties, including some NSAIDs, Minocycline and Atorvastatin, could lead to promising and intriguing results in the treatment of OCD. Curcumin also showed good efficacy in the reduction of OCD-like behavior when it has been used in an animal model. However, there is still no definitive and conclusive evidence for any of the medications proposed. Conclusion: More future studies are needed to investigate anti-inflammatory treatment strategies for OCD and its other subtypes such as Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS), and Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS).

Background: Bcl-2 family plays an essential role in the cell cycle events incorporating survival, proliferation, and differentiation in normal and neoplastic neuronal cells. Thus, it has been validated as a principal target for the treatment of cancer. For this reason, we will build a model based on a large number of Bcl-2 inhibitors to predict the activities of new compounds as future Bcl-2 inhibitors. Methods: In this study, QSAR models were successfully used to predict the inhibitory activity against Bcl-2 for a set of compounds collected from BDB (Binding database). The kPLS (kernelbased Partial Least-Square) method implemented in Schrodinger's Canvas, was used for searching the correlation between pIC50 and binary fingerprints for a set of known Bcl-2 inhibitors. Results and Discussion: Models based on binary fingerprints with two kPLS factors have been found with decent predictive power (q² > 0.58), while the optimal number of factors is about 5. The enrichment study (148 actives, 5700 decoys) has shown excellent classification ability of our models (AUC > 0.90) for all cases). Conclusion: We found that the kPLS method, in combination with binary fingerprints, is useful for the affinity prediction and the Bcl-2 inhibitors classification. The obtained promising results, methods, and applications highlighted in this study will help us to design more selective Bcl-2 inhibitors with better structural characteristics and improved anti-cancer activity.

Background: α-Glucosidase inhibitors hinder the carbohydrate digestion and play an important role in the treatment of diabetes mellitus. α-glucosidase inhibitors available on the market are acarbose, miglitol, and voglibose. However, the use of acarbose is diminishing due to related side effects like diarrhea, bloating and abdominal distension. Objectives: This study aimed to synthesize 2,4,6-triaryl pyrimidines derivatives, screen their α- glucosidase inhibitory activity, perform kinetic and molecular docking studies. Methods: A series of 2,4,6-triaryl pyrimidine derivatives were synthesized and their α-glucosidase inhibitory activity was screened in vitro. Pyrimidine derivatives 4a-m were synthesized via a twostep reaction with a yield between 49 and 93%. The structure of the synthesized compounds was confirmed by different spectroscopic techniques (IR, NMR and MS). The in vitro α-glucosidase inhibition activities of the synthesized compounds 4a-m was also evaluated against Saccharomyces cerevisiae α-glucosidase. Results and Discussion: The majority of synthesized compounds had α-glucosidase inhibitory activity. Particularly compounds 4b and 4g were the most active compounds with an IC50 value of 125.2± 7.2 and 139.8 ± 8.1 μM respectively. The kinetic study performed for the most active compound 4b revealed that the compound was a competitive inhibitor of Saccharomyces cerevisiae α-glucosidase with Ki of 122 μM. The molecular docking study also revealed that the two compounds have important binding interactions with the enzyme active site. Conclusion: 2,4,6-triarylpyrimidine derivative 4a-m were synthesized and screened for α- glucosidase inhibitory activity. Most of the synthesized compounds possess α-glucosidase inhibitory activity, and compound 4b demonstrated the most significant inhibitory action as compared to acarbose.

Background: Benzimidazole derivatives are privileged molecules known to have a wide variety of biological activities. In medicinal chemistry, due to the ring’s structural similarity to nucleotides, its derivatives were investigated as new chemotherapeutic agents. Our research group have been studying 1,2-disubstituted benzimidazoles, including thiocarbamoyl group and their potential anticancer activity. Based on previous findings, we synthesized novel 1-[2-(4-substituted phenyl-2-oxoethyl)]-2-[(2/3/4-substituted phenylpiperidin-1-yl)thiocarbamoyl]benzimidazole derivatives (3a-o). Methods: The obtained fifteen derivatives were studied on A549 adenocarcinomic human alveolar basal epithelial cell line and mouse L929 fibroblastic cell line to determine their cytotoxic activity. These compounds were also investigated to identify their apoptotic properties. Results and Discussion: The structures of the compounds based on three different groups differ from each other with the phenyl substituents bonded to the piperazine ring. All of the compounds showed remarkable antitumor activity, but the first five compounds bearing non-substituted phenyl moiety exhibited selective cytotoxicity when compared in terms of potencies to the normal cell line. Conclusion: Compounds 3j, 3m and 3n were identified as the most apoptotic derivatives; however, compounds 3e and 3h provoked apoptosis with the percentages of 10.6 and 10.9% and selective cytotoxicity.

Background: The researchers of PIBOC RAS developed the dermo-protective topical drug called «Kourochitin», active substance of which is known quinazoline alkaloid tryptanthrin. In the present work, therapeutic efficacy of this drug in the treatment of allergic dermatosis was evaluated. Methods: Dermo-protective action of «Kourochitin» was studied in tow murine models: 2, 4- dinitrofluorobenzene- induced allergic contact dermatitis (ACD) and imiquimod-induced psoriasis. Results and Discussion: In a model ACD, it was shown that «Kourochitin» exhibits the curative action on pathophysiological, hematological and immunological parameters in ACD. Namely, «Kourochitin» 1) reduces the level of erythema in the allergen damaged skin area and increases the healing index of the epidermis; 2) normalizes the content of eosinophils, basophils and monocytes in the blood of experimental animals; 3) inhibits the production of main pro-inflammatory cytokines: interleukins - 1 and 2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. In a murine model of imiquimod-induced psoriasis, it was shown that «Kourochitin» application led to reduction in psoriasis severity on the inflamed epidermis of experimental animals. Additionally, in veterinary research, «Kourochitin»-treatment of canine atopic dermatitis almost completely eliminated signs of allergic manifestations on the epidermis. Conclusion: The obtained data suggest that «Kourochitin» as anti-inflammatory, anti-allergic, and wound healing remedy is a potential drug for therapy of various dermatological diseases, in particular allergic skin lesions.

Background: The role of α, β unsaturated propenone derivatives, has attracted the chemists for its biological importance. An attempt is made to reveal the interaction between breast and skin cancer cell lines with the help of molecular docking studies. Objective: The study aimed to synthesize and characterize 4-ethoxychalcones for testing breast and skin cancer targets. Methods: A series of chalcone analogues starting from 4-ethoxyacetophenone and substituted aromatic aldehydes were synthesized, well-characterized and evaluated for their in vitro anticancer activities against human breast cancer (MDA-MB-231) and human metastatic melanoma (A-375) cell lines by MTT assay. Docking simulation was performed to study the drug-receptor interaction of chalcone scaffold on the active site of target inhibitor bound to cytochrome P450 family oxidoreductase for breast cancer and Pirin inhibiting target for skin cancer, respectively. Results and Discussion: After performing cytotoxic evaluation, it was observed that compounds having a substitution at the para position showed better results compared to ortho and meta positions for both the cell lines. Molecular docking studies revealed different types of interactions with selected oxidoreductase and Pirin inhibiting targets. Ligand-protein interactions and morphological changes are monitored by molecular dynamics. Conclusion: The presence of electron-withdrawing and donating groups on ring B marginally affected IC50 and docking scores. The stability of the binding mode of ligands having high inhibitory efficiency for compounds 8 and 10 predicted by docking studies was confirmed by molecular dynamics simulation. The pharmacokinetic parameters were found to be within the acceptable range. Further molecular dynamics study would provide the necessary information.

Background: Parkinson’s disease is a common neurodegenerative disorder characterized by selective loss of dopaminergic neurons in the substantia nigra pars compacta. Introduction: The effects of alpha synuclein, parkin mutation and pharmacological agents have been studied in the Drosophila model. Methods: The effect of cabergoline was studied on the cognitive impairments exhibited by the transgenic Drosophila expressing human alpha-synuclein in the neurons. The PD flies were allowed to feed on the diet having 0.5, 1 and 1.5 μM of cabergoline. Results and Discussion: The exposure of cabergoline not only showed a dose-dependent significant delay in the cognitive impairments but also prevented the loss of dopaminergic neurons. Molecular docking studies showed the positive interaction between cabergoline and alpha-synuclein. Conclusion: The results suggest a protective effect of cabergoline against the cognitive impairments.

Background: P-glycoprotein (P-gp) has been regarded as an important factor in the multidrug resistance (MDR) of tumor cells within the last decade, which can be solved by inhibiting Pgp to reverse MDR. Thus, it is an effective strategy to develop inhibitor of P-gp. Objective: In this study, the synthesis of a series of derivatives had been carried out by bioisosterism design on the basis of Dimethyl Cardamonin (DMC). Subsequently, we evaluated their reversal activities as potential P-glycoprotein (P-gp)-mediated Multidrug Resistance (MDR) agents. Methods: Dimethyl cardamonin derivatives were synthesized from acetophenones and the corresponding benzaldehydes in the presence of 40% KOH by Claisen-Schmidt reaction. Their cytotoxicity and reversal activities in vitro were assessed with MTT. Moreover, the compound B4 was evaluated by Doxorubicin (DOX) accumulation, Western blot and wound-healing assays deeply. Results and Discussion: The results showed that compounds B2, B4 and B6 had the potency of MDR reversers with little intrinsic cytotoxicity. Meanwhile, these compounds also demonstrated the capability to inhibit MCF-7 and MCF-7/DOX cells migration. Besides, the most compound B4 was selected for further study, which promoted the accumulation of DOX in MCF-7/DOX cells and inhibited the expressionof P-gp at protein levels. Conclusion: The above findings may provide new insights for the research and development of Pgp- mediated MDR reversal agents.

Background: Phenolic Mannich bases have been reported as acetylcholinesterase (AChE) inhibitors for the medication of Alzheimer's disease. Carbonic Anhydrases (CAs) are molecular targets for anticonvulsant, diuretic and antiglaucoma drugs in the clinic. Phenolic compounds have also been mentioned as CA inhibitors. The importance of Mannich bases in drug design inspired our research group to design novel phenolic Mannic bases as potent enzyme inhibitors. Objective: In this study, novel Mannich bases, 1-(3,5-bis-aminomethyl-4-hydroxyphenyl)-3-(4- substitutedphenyl)-2-propen-1-ones (1-9), were designed to discover new and potent AChE inhibitors for the treatment of Alzheimer's disease and also to report their carbonic anhydrase inhibitory potency against the most studied hCA I and hCA II isoenzymes with the hope to find out promising enzyme inhibitors. Methods: Mannich bases were synthesized by the Mannich reaction. The structures of the compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Enzyme inhibitory potency of the compounds was evaluated spectrophotometrically towards AChE, hCA I and hCA II enzymes. Results and Discussion: The compounds showed inhibition potency in nanomolar concentrations against AChE with Ki values ranging from 20.44±3.17 nM to 43.25±6.28 nM. They also showed CAs inhibition potency with Ki values in the range of 11.76±1.29-31.09±2.7 nM (hCA I) and 6.08 ± 1.18-23.12±4.26 nM (hCA II). Compounds 1 (hCA I), 5 (hCA II), and 4 (AChE) showed significant inhibitory potency against the enzymes targeted. Conclusion: Enzyme assays showed that Mannich derivatives might be considered as lead enzyme inhibitors to design more selective and potent compounds targeting enzyme-based diseases.

Background: Treatments of fungal diseases, including Candidiasis, remain not up to scratch in spite of the mounting catalog of synthetic antifungal agents. These have served as the impetus for investigating new antifungal agents based on natural products. Consequently, genetic algorithm-multiple linear regression (GA-MLR) based QSAR (Quantitative Structure-Activity Relationship) studies of coumarin analogues along with molecular docking were carried out. Methods: Coumarin analogues with their MIC values were used to generate the training and test sets of compounds for QSAR models development; the analogues were also docked into the binding pocket of NMT (MyristoylCoA: protein N-myristoyltransferase). Results and Discussion: The statistical parameters for internal and external validation of QSAR analysis (R² = 0.830, Q² = 0.758, R²Pred = 0.610 and R²m overall = 0.683 ), Y Randomization, Ridge trace, VIF, tolerance and model criteria of Golbraikh and Tropsha data illustrate the robustness of the best proposed QSAR model. Most of the analogues bind to the electrostatic, hydrophobic clamp and display hydrogen bonding with amino acid residues of NMT. Interestingly, the most active coumarin analogue (MolDock score of -189.257) was docked deeply within the binding pocket of NMT, thereby displaying hydrogen bonding with Tyr107, Leu451, Leu450, Gln226, Cys393 and Leu394 amino acid residues. Conclusion: The combinations of descriptors from various descriptor subsets in QSAR analysis have highlighted the role of atomic properties such as polarizability and atomic van der Waals volume to explain the inhibitory activity. The models and related information may pave the way for important insight into the designing of putative NMT inhibitors for Candida albicans.

Aims: Medicinal plants like Citrullus colocynthis are a potential choice to produce helpful novel antimycobacterial drugs. The existence of a range of natural products in the plants, especially Ursolic Acid (UA) and cucurbitacin E 2-0-β-d-glucopyranoside (CEG), with promising antibacterial activity against a variety of bacteria, prompted the need to check its actions against Mycobacterium tuberculosis (Mtb). Background: Mycobacterium tuberculosis (Mtb), an obligate human pathogen causes tuberculosis and is one of the major causes of death worldwide. A few combinations of drugs are currently accessible for treating TB patients, but these are inadequate to tackle worldwide TB cases. Objective: The molecular interactions between ursolic acid and cucurbitacin E with the eight potential Mtb target proteins were investigated with the objective of finding drug-like inhibitors. Methods: Avogadro v.1.2.0 and Openbabel v.2.4.1 were used for creating file formats required for docking analysis. Molecular docking was performed with eight different proteins essential for Mtb metabolism and survival. AutoDock v.4.2 and AutoDock vina v.1.1.2 were used for docking and Gromacs 5.1.4 was used for simulation studies. Results and Discussion: Among the two ligands used in this research, cucurbitacin E showed a better docking score relative to the drugs presently available for all the target proteins. Rifampicin showed the best binding affinity (among known inhibitors) i.e. -10.8 kcal/mol with C terminal caspase recruitment domain. Moreover, ursolic acid and cucurbitacin E showed uniform binding score (above -7.5 kcal/mol) with all the target proteins, acknowledged its availability as a potential multi-target drug. Conclusions: Ursolic acid can be useful in the creation of novel, multi-targeted and effective anti- TB medicines since it showed stable structure with FabH.

Background: Ovarian cancer and ovarian related diseases affect reproductive health. Therapeutic molecules are needed to improve treatment outcomes and overcome drug resistance. The benzimidazole-based sulphonamide LLW-3-6 has both anti-apoptotic and anti-proliferative effects when used to treat prostate, breast, and brain cancer cells. Objective: The study described herein evaluates the anti-proliferative and anti-migratory effects of LLW-3-6 in SKOV-3 ovarian cystadenocarcinoma cell line. Methods: Studies were conducted using SKOV-3 cells treated with LLW-3-6. The cell line was propagated and proliferative activity was evaluated by hemocytometric and MTT colorimetric assays. Cellular apoptosis was assessed using caspase-3 spectrophotometric analysis. Lastly, a scratch wound assay was conducted at several concentrations and time points to assess the effect of LLW-3-6 on migration. Results & Discussion: Proliferative studies suggest, SKOV-3 cells exposed to LLW-3-6 in culture resulted in decreased growth and proliferation of cells in a time and dose-dependent manner. The apoptotic effect of this agent was noted with the confirmed presence of Caspase-3 in a dose and time-dependent manner as well. Preliminary studies also suggest an anti-migratory effect of LLW-3- 6, confirmed by scratch wound analysis. Conclusion: LLW-3-6 is potentially a chemotherapeutic option for decreasing proliferation and inducing apoptosis in ovarian carcinomas. Additional biological analysis are ongoing to further assess the utility of the molecule and its mechanism of action.

Background: SARS-CoV-2 causes COVID19 disease where there are no suitable drugs available. Objective: The objective of the work is to repurpose the drugs prescribed for SARS-CoV as the drugs for the control of SARS-CoV-2. Methods: In this work, we have used homology searches and docking methods for understanding the mechanism of the drugs prescribed for the control of SARS-CoV on SARS-CoV-2. Results: In our analysis, we found that the drugs Benzyl (2-Oxopropyl)carbamate, 2-[(2,4-Dichloro- 5-methyl phenyl)sulfonyl]-1,3-dinitro-5-(trifluoromethyl)benzene, S-[5-(Trifluoromethyl)-4H-1,2,4- triazol-3-YL] 5-(phenylethynyl)furan-2-carbothioate, 4-(Dimethylamino)benzoic acid, which are capable of inhibition of the activity of 3CLPro and prevent the progression of SARS-CoV. Conclusion: In this letter, we describe the findings of the protein ligand interactions between 3CLPro of SARS-CoV, SARS-CoV-2 with Benzyl (2-oxopropyl) carbamate.