Current Drug Discovery Technologies - Volume 17, Issue 2, 2020

Background: Vitiligo is a pigmentary disorder characterizing by white macules due to loss of melanocytes. Vitiligo affects about 1 to 4% of people around the world. The treatment of vitiligo has a high cost and the long process of treatment in spite of no complete remedy. It has various psychological side-effects such as depression and anxiety affecting the quality of life seriously. Avicenna in his Canon treated these patients over a thousand years ago. This study aimed to introduce some herbal drugs in vitiligo based on the Canon of Avicenna besides the conventional medical treatments. Methods: This is a review study, according to the Canon with the term Baras and also searching through the electronic websites with the keywords vitiligo, treatment, and herbal drugs. Results: The study found some herbs affecting the vitiligo from the Canon. Conclusion: The researchers suggest conducting clinical trials on the patients with vitiligo based on the Canon besides the conventional techniques to obtain a better result in the treatment.

Cardiovascular Disease (CVD) remains the leading cause of morbidity and mortality in the western world. Hypolipidemic drugs have long been used for the primary and secondary prevention of heart disease. However, the high frequency of recurrent events in patients despite hypolipidemic therapy has increased the need for new more targeted therapeutic approaches. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are monoclonal antibodies to the PCSK9 gene and represent a new class of drugs that have been shown to further decrease LDL-C when administered as a monotherapy or in combination with statins. In addition to LDL reduction, PCSK9 inhibitors are shown to decrease apolipoprotein B and lipoprotein (a) levels without major adverse effects. Whether or not PCSK9 inhibitors can actually reduce the incidence of cardiovascular events and ameliorate CVD prognosis is yet to be clarified. This review summarizes recent literature on the safety and efficacy of PCSK9 inhibitors on CVD outcome and its potential role in the management of patients with high-risk cardiovascular disease.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB), still remains a deadly disease worldwide. With prolonged usage of anti-TB drugs, the current therapeutic regimes are becoming ineffective, particularly due to emergence of drug resistance in MTB. Under such compelling circumstances, it is pertinent to look for new drug targets. The cell wall envelope of MTB is composed of unique lipids that are frequently targeted for anti-TB therapy. This is evident from the fact that most of the commonly used front line drugs (Isoniazid and Ethambutol) act on lipid machinery of MTB. Thus, despite the fact that much of the attention is towards understanding the MTB lipid biology, in search for identification of new drug targets, our knowledge of bacterial cell wall non-lipid components remains rudimentary and underappreciated. Better understanding of such components of mycobacterial cell structure will help in the identification of new drug targets that can be utilized on the persistent mycobacterium. This review at a common platform summarizes some of the non-lipid cell wall components in MTB that have potential to be exploited as future drug targets.

Background: In the past decade CADD has emerged as a rational approach in drug development so with the help molecular docking approach we planned to perform virtual screening of the designed data set of Schiff bases of cinnamaldehyde. The research work will be helpful to put some light on the drug receptor interactions required for anti-inflammatory activity. Methods: For carrying out virtual screening of the developed cinnamaldehyde Schiff base data set, AutoDock 4.0 was used. The active hits identified through in silico screening were synthesized. Anti-inflammatory evaluation was carried out using Carrageenan-induced paw oedema method. Results: Compounds V2A44, V2A55, V2A76, V2A82, V2A119, V2A141 and V2A142 has shown highest binding energy (-4.84, -4.76, -4.59, -4.78, -4.74, -4.85 and -4.72 kcal/mol, respectively) and the binding interactions with amino acids namely, Phe478, Glu479, Lys492, Ala493, Asp497 and Ile498. Some of the analogs have shown significant activity and were comparable to Indomethacin (standard drug). Conclusion: Five new compounds have shown significant activity and the results obtained from in silico studies are parallel to those of in vivo studies.

Background: Some lactones prevent protein Myb-dependent gene expression. Objective: The object is to calculate inhibitors of Myb-brought genetic manifestation. Methods: Linear quantitative structure–potency relations result expanded, among sesquiterpene lactones of a variety of macrocycles (pseudoguaianolides, guaianolides, eudesmanolides and germacranolides), to establish which part of the molecule constitutes their pharmacophore, and predict their inhibitory potency on Myb-reliant genetic manifestation, which may result helpful as leads for antileukaemic therapies with a new mechanism of action. Results: Several count indices are connected with structure–activity. The α-methylene-γ-lactone ML functional groups increase, whereas OH groups decrease the activity. Hydrophobicity provides to increase cell toxicity. Four counts (ML, number of α, β-unsaturated CO groups, etc.), connected with the number of oxygens, present a positive association, owing to the partial negative charge of oxygen. The s-trans-strans- germacranolide molecule presents maximal potency. The OH groups decrease the potency owing to the positive charge of hydrogen. The numbers of π-systems and atoms, and polarizability increase the potency. Following least squares, every standard error of the coefficients is satisfactory in every expression. The most predictive linear expressions for lactones, pseudoguaianolides and germacranolides are corroborated by leave-group-out cross-validation. Quadratic equations do not make the correlation better. Conclusion: Likely action mechanisms for lactones are argued with a diversity of functional groups in the lactone annulus, including artemisinin with its uncommon macrocycle characteristic, 1,2,4-trioxane cycle (pharmacophoric peroxide linkage -O1-O2- in endoperoxide ring), which results in the foundation for its sole antimalarial potency.

Background: Tubulin is the biochemical target for several clinically used anticancer drugs as it helps in the formation of mitotic spindle during mitosis stage of cell division. Many of the anti-cancer drugs are known to interact with tubulin and microtubules including some plant alkaloids, such as paclitaxel, etoposide and topotecan. In silico drug design of these molecules were performed prior to testing these drugs in vitro. In silico drug design of these anti-cancer drugs becomes a challenge due to the complex structure of target protein. This challenge was overcome by predicting the structure of the target protein (tubulin) by homology modeling. Methods: In this study, computer aided drug designing approach was applied to predict the suitable docking site in target protein and the interaction of tubulin protein with paclitaxel, etoposide and topotecan was explored by molecular docking using Schrödinger software. Docking score and glide energy were determined with ligands to validate their anticancer properties. Results: The results indicate that etoposide is the best drug for tubulin with a docking score of - 4.916 and glide energy of -46.470 kcal/mol compared to paclitaxel and topotecan. Conclusion: The testing of these drugs in silico provides an alternate to in vitro testing of these molecules on cancer cell lines which is a time and cost intensive process. The in silico study of parameters, such as docking score and glide energy, will help pharmacists in developing new molecules as targets for cancers in a time and cost-effective manner.

Background: Uropathogenic Escherichia coli (UPEC) is a major cause of Urinary Tract Infections (UTIs). Due to increasing antibiotic-resistance among UPEC bacteria, new treatment options for UTIs are urgently needed. Objective: To identify new agents targeting growing bacteria that may be used for the treatment of antibiotic-resistant UTIs. Methods: We screened a clinical compound library consisting of 1,524 compounds using a high throughput 96-well plate assay and ranked the activities of the selected agents according to their MICs against the UPEC strain UTI89. Results: We identified 33 antibiotics which were active against log-phase clinical UPEC strain UTI89. Among the selected antibiotics, there were 12 fluoroquinolone antibiotics (tosufloxacin, levofloxacin, sparfloxacin, clinafloxacin, pazufloxacin, gatifloxacin, enrofloxacin, lomefloxacin, norfloxacin, fleroxacin, flumequine, ciprofloxacin), 15 beta-lactam or cephalosporin antibiotics (cefmenoxime, cefotaxime, ceftizoxime, cefotiam, cefdinir, cefoperazone, cefpiramide, cefamandole, cefixime, ceftibuten, cefmetazole, cephalosporin C, aztreonam, piperacillintazobactam, mezlocillin), 3 tetracycline antibiotics (meclocycline, doxycycline, tetracycline), 2 membrane-acting agents (colistin and clofoctol), and 1 protein synthesis inhibitor (amikacin). Among them, the top 7 hits were colistin, tosufloxacin, levofloxacin, sparfloxacin, clinafloxacin, cefmenoxime and pazufloxacin, where clinafloxacin and pazufloxacin were the newly identified agents active against UPEC strain UTI89. We validated the key results obtained with UTI89 on two other UTI strains CFT073 and KTE181 and found that they all had comparable MICs for fluoroquinolones while CFT073 and KTE181 were more susceptible to cephalosporin antibiotics and tetracycline antibiotics but were less susceptible to colistin than UTI89. Conclusion: Our findings provide possible effective drug candidates for the more effective treatment of antibiotic-resistant UTIs.

Background: In medicinal chemistry, the discovery of small organic molecules that can be optimized and lead to a future drug capable of effectively modulating the biological activity of a therapeutic target remains a major challenge. Because of the harmful secondary effects of synthesized therapeutic molecules, the development of research has been oriented towards phytomedicines. Phenolic compounds from medicinal plants are constantly explored for new therapeutic use. Methods: In this paper, we studied interactions between main enzymes responsible for causing type 2 diabetes mellitus (T2DM) and phenolic compounds from nettle (Urtica dioica L.) using molecular Docking with Molecular Operating Environment Software (MOE). Results: Docking results show a common molecule (secoisolariciresinol), which may form stable complexes with depeptidyl peptidase 4 (DPP-4), alpha-amylase and beta-glucosidase with binding energy of -7.04732084 kcal/mol, -3.82946181 kcal/mol and -4.16077089 kcal/mol respectively. Besides secoisolariciresinol, other phenolic compounds give better docking score than the original co-crystallized ligand for alpha-amylase (PDB ID 5U3A) and beta-glucosidase (PDB ID 1OGS). Conclusion: The obtained results are promising for the discovery of new alpha-amylase and betaglucosidase inhibitors. This study also confirms the folk use of nettle as antidiabetic agent.

Background: According to WHO, in 2017, about 90.5 million people suffered from cancer and about 8.8 million deaths occurred due to disease. Although the chemotherapeutic agents have decreased the mortality among the cancer patients but high toxicity and non-specific targets are still major drawbacks. Many researchers have identified linomide, a 4-hydroxy-2-quinolone derivative, as a lead molecule for the development of anticancer agents. With this background, we thought of the following objective. Objective: The objective of this research work involves the synthesis of a series of N-(2-(4- hydroxy-2-oxo-1-phenyl-1,2-dihydroquinolin-3-yl)-2-oxoethyl)-N-alkyl substituted benzene sulfonamides IVa-d (1-3) by replacing the anilide moiety at the third position of linomide with sulfamoylacyl and also N-methyl by N-phenyl functionality. To perform in silico anticancer activity by using Molegro Virtual Docker (MVD-2013, 6.0) software and in vitro anticancer activity by MTT assay. Methods: The starting material 4-hydroxy-1-phenylquinolin-2(1H)-one was treated with N-bromosuccinamide to yield compound II. Condensation of compound II with primary amines resulted in compounds IIIa-d, which, on coupling with substituted aromatic sulfonyl chlorides yield the title compounds IVa-d (1-3). Results: All the synthesized compounds were satisfactorily characterized by spectral data. The results of docking revealed that the synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of EGFRK tyrosine kinase domain (PDB ID: 1m17). The MolDock Score of compound IVd-1 (-115.503) was the highest amongst those tested. The in vitro anticancer activity results showed that compound IVc-1 (R= - (CH2) 2-CH3 ; R′= -H) and IV d-1 (R= -CH2-C6H5; R′= -H) were found to be most potent against K562 cell line with an IC50 of 0.451 μM/ml and 0.455 μM/ml respectively. Compound IVd-1 also showed better potency against A549 cell line with IC50 value of 0.704 μM/ml. Conclusion: The results of in silico and in vitro anticancer activity are in agreement with each other. Compound IV d-1 was found to be most active of the series.

Background: The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity. This strategy of designing compounds possessing selectivity over specific tyrosine kinase has been achieved through G-QSAR and molecular docking studies. Methods: The objective of this research has been to design newer 2-phenazinamine derivatives as Bcr-Abl tyrosine kinase inhibitors by G-QSAR, molecular docking studies followed by wet lab studies along with evaluation of their anticancer potential. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2 followed by wet lab experiments for synthesizing 2- phenazinamine derivatives. The chemical structures of ligands in 2D were drawn by employing Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimised by using semiempirical method called MOPAC. The protein structure was retrieved from RCSC protein data bank as PDB file. The binding interactions of protein and ligands were done by using PYMOL. The molecular properties of the designed compounds were predicted in silico by using Osiris property explorer. Later, we synthesized novel 13 2-phenazinamine derivatives by treating parent compound with various aldehydes in the presence of dicyclohexylcarbodiimide (DCC) and urea to afford 2-(2-chlorophenyl)-3-(phenazin-2-yl) thiazolidin-4-one and another series of derivatives synthesized with different aldehydes in the presence of p-toluylsulphonic acid, diphydropyridine and benzene sulfonyl chloride to afford benzenesulfonyl-N-(2-chlorobenzyl)-phenazin-2-amine. All the derivatives were tested for invitro anticancer activity on K562 human chronic myelogenous leukemia cell line by employing MTT assay method. Results: The developed G-QSAR models were found to be statistically significant with respect to training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892). The best developed G-QSAR model suggested that the XlogP values of phenazinamine derivatives were found to be highly influential in determining biological activity. The standard drug was found to exhibit binding energy - 6.79 kcal/mol and the derivatives 5b and 6c exhibited binding energy of - 7.46 and - 8.51; respectively. Conclusion: Compounds 5b, 6c were observed to possess good lipophilicity and were found to exhibit better activity than other compounds in the series, although less than standard doxorubicin. The synthesis of these 2-phenazinamine derivatives (5a-m) is reported to be obtained from 2,4- dinitrodiphenylamine by applying appropriate synthetic route. Compounds 5b and 6c showed better cytotoxic activity against K562 cancer cell line when compared to other compounds of the series, although less than standard doxorubicin.

Objective: This investigation evaluates the pro-apoptotic and anti-inflammatory effects of β-D-mannuronic acid [M2000] compared to diclofenac, based on gene expression involved in apoptosis and inflammation process [including Bcl2, NFΚB, IL-8 and Cd49d] in Peripheral Blood Mononuclear Cells [PBMCs] of healthy donors under exvivo conditions. Materials: The venous blood samples of twelve healthy volunteers with aged 25-60 years were collected in heparinized tubes. The healthy volunteers were selected from no smoking group and without using illicit drugs and suffering from diabetes. The PBMCs were separated and divided into untreated and treated groups. Methods: The PBMCs of each sample were cultured in 5 wells of culture plate, so that the first well consisted of 2x106 cells exposed by LPS-EB [1μg/ml] to stimulate PBMCs and absence of M2000 [untreated well]. The second, third, fourth and fifth wells containing 2x106 cells/well and LPS-EB, after 4 hours incubation at 37ºC, received 5, 25 and 50 μg/well of M2000 and 5 μg/well of diclofenac, respectively as treated group. Results: The PBMCs were separated and RNAs were then extracted and cDNAs synthesized and gene expression levels were assessed by qRT-PCR. Furthermore, we studied whether M2000 is able to facilitate apoptosis in PBMCs. Our findings represent that the high dose of M2000 could significantly decrease the expression level of NFΚB gene compared to untreated group (p < 0.0002). On the other hand, no significant change was observed in treated cells with diclofenac. All doses of M2000 could significantly augment apoptosis compared to untreated group [p < 0.0001]. Additionally, we observed the same apoptotic effects between the medium dose of M2000 and diclofenac. Besides, no significant reduction was shown in expression levels of IL8, Bcl2 and Cd49d genes in all doses of M2000 and diclofenac compared to untreated group. This experiment demonstrates M2000 as a new effective NSAID with immunosuppressive characteristics capable of stimulating apoptosis through lowering expression levels of NFΚB gene, which might be probably considered as an appropriate drug for reducing the risk of developing inflammatory diseases and cancer.

Background: Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators. Methods: DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software. Results and Conclusion: Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

Introduction: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identify the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity. Materials and Methods: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the targets. A data set comprising 18 analogues of curcumin, was used as ligands for docking of PDE4 subtypes. Curcumin was used as the standard for comparison. Docking was performed using AutoDock Vina 1.1.2 software integrated in LigandScout 4.1. During this process water molecules were removed from proteins, charges were added and receptor structures were minimised by applying suitable force fields. The docking scores were compared, and the selectivity of compounds for PDE4B over PDE4D was calculated as well. Results: All curcumin analogues used in the study showed good binding affinity with all PDE4 subtypes, with evident selectivity towards PDE4B subtype. Analogue A11 provides the highest binding affinity among all ligands. Conclusion: Curcumin and analogues have moderate to strong affinity towards all PDE4 subtypes and have evident selectivity towards PDE4B. The Oxygen atom of the methoxy group plays a key role in PDE4B binding and any alterations could interfere with the binding. Tetrahydropyran side chain and heterocyclic rings are also suggested to be helpful in PDE4B binding.