Letters in Drug Design & Discovery - Volume 14, Issue 11, 2017

Background: Cancer is becoming an increasingly important risk factor in the global burden of diseases. Cancer chemotherapy has been one of the major medical advances in the last few decades. However, the drugs used for this therapy have a narrow therapeutic index, and often the responses produced are only just palliative as well as unpredictable. In contrast, targeted therapy that has been introduced in recent years is directed against cancer-specific molecules and signaling pathways and thus has more limited nonspecific toxicities. This paper reviews about 2D, 3D QSAR and G-QSAR on a set of thiazolyl-pyrazole derivatives to identify novel and potent EGFR-TK inhibitors and elucidate structural properties required for anti-EGFR-TK activity. The 2D QSAR studies were carried out by multiple regression method and the r2 and q2 values were found to be 0.81 and 0.72 respectively. The 3D QSAR was performed using method k-nearest neighbour–molecular field analysis (kNN-MFA) with simulated annealing variable selection approach; a leave-one-out crossvalidated correlation coefficient q2 = 0.87 and non-cross-validated correlation coefficient r2 = 0.93. G-QSAR was performed by generation of multiple models of the same training and test sets as used in 2D & 3D QSAR by multiple linear regressions. G-QSAR was carried out using template based fragmentation scheme and forward variable selection method. Docking analysis was performed further and is suggestive of binding affinity with standard compounds. Methods: Molecular modeling, structure based drug design and docking analysis studies were performed. Initially molecular modeling studies (2D, 3D and G-QSAR) were performed on a set of thiazolyl-pyrazole derivatives. A lead nucleus was predicted and with the help of CombiLib; VLife MDS and Lipinski's screen 12 novel chemical entities (NCE’s) were designed. They were then subjected to docking and were further filtered. Five compounds having potent EGFR activity having drug like pharmacokinetic profiles were predicted. Results: The lead nucleus required for anti-EGFR activity could be predicted. The NCE's could then be designed, docked. Erlotinib was considered as the docking standard and it was found that these compounds mimic Erlotinib and bind to the same amino acids pocket region of active binding site of Erlotinib in PTK receptors with much higher affinities involving more number of H bonds with shorter measure, higher number of good vdW bonds and lesser number of/number bad/ugly vdW interactions. Thus they show enzyme specificity and are developed as selective PTK inhibitors having potent anticancer activity. These compounds with potent anticancer (anti-EGFR activity) along with their Absorption, Distribution, Metabolism, and Excretion (ADME) properties by means of Qikprop 2.2 Tool of, Schrodinger, could be successfully predicted having drug like pharmacokinetic profile. Conclusion: Molecular modeling is one of the most successful and rapidly growing techniques. It not only helps in predicting target specific compounds but also helps in reducing cost of valuable chemicals. In this study successful use of molecular modeling was done and caution was taken to avoid any chance co-relation. Optimization was done to obtain lead nucleus and after designing NCE's and docking five compounds with potent anti-EGFR activity and drug like pharmacokinetic profile could be successfully predicted.

Background: Peroxisome proliferator-activated receptor (PPAR) δ is a type of PPARs belonging to the steroid or nuclear hormone receptor super family. Activation of PPARδ leads to metabolism of fat instead of glucose by body for energy requirements. PPARδ represent an emerging pharmacological target for the treatment of metabolic syndrome (MS). Many selective and potent PPARδ agonists had been synthesized with a potential role in the treatment of various disorders associated with MS including type 2 diabetes and inflammation. Objective: The present work was designed to synthesize and evaluate the antidiabetic and anti-inflammatory activity of some newer phenylacetic acid and trifluoromethylphenyl substituted benzamide derivatives as potential PPARδ agonists. Methods: This work involved the synthesis of newer sulfamoyl benzamide derivatives and their evaluation by molecular docking studies to determine the binding interactions for the best fit conformations in the binding site of the PPARδ protein. Based on the results of the in silico studies, the selected compounds were tested for their antidiabetic and anti-inflammatory activity in the animal models. Results: Amongst the synthesized molecules, compound 7 showed higher anti-diabetic activity and compound 19 showed higher anti-inflammatory activity. The experimental results were found to be in concordance with that of the in silico results. Most of the synthesized molecules were found to have drug like properties as devised by Lipinski's rule of five. Conclusion: These molecules can act as the starting hits for the design of safe, effective and bioavailable PPARδ agonists for the potential treatment of MS and related diseases.

Background: Heterocyclic system is a common structure feature of widely used drugs such as anticancer, anticonvulsant, antieplipeptic, and antiparastic agents. Methods: Structure-based drug design and Glide docking studies were employed to rationalize the toxicity of a new series of thiosemicarbazone-based indole derivatives against human colon carcinoma (HCT116) cell line. Results: Glide docking studies showed that the verified compounds fit PI3Kα kinase catalytic site and form H-bonding with K802, Y836, V851, S854, Q859, S919, and D933. The pharmacophore modeling of PI3Kα active inhibitors displayed that verified compounds matched four out of five functionalities of PI3Kα inhibitors. Conclusion: Our findings suggest that further optimization of the core structure of this series would be beneficial for colon cancer treatment.

Background: Aromatase is an enzyme that plays a critical role in the development of estrogen receptor positive breast cancer. As aromatase catalyses the aromatization of a drostenedione to estrone, a naturally occurring estrogen, it is a promising drug target for therapeutic management. Objective: The objective of the present study is to evaluate the binding interaction of flavonoid compounds with cytochrome P450 enzyme aromatase and also checked ADME/T properties of best scored compounds. Methods: To examine different molecules for this purpose, test ligands like Flavonoids derivatives were docked against our target protein aromatase enzyme retrieved from protein data bank (PDB Id: 3S7S), considering Exemestane as the positive control. Results: Docking results revealed that, with respect to their free binding energy 6B, 6K, 4K and 2K compounds have the lowest binding energy compared to positive control. In silico ADME/T predictions revealed that all best scored compounds had good absorption as well as solubility characteristics. Conclusion: The present findings provided valuable information on the binding process of flavonoid compounds to the binding site of aromatase. These compounds may serve as potential lead compounds for developing new aromatase inhibitors in breast cancer treatment.

Background: Oxametacin is a non-steroidal anti-inflammatory drug with pharmacophores of classic histone deacetylase inhibitors. To evaluate the histone deacetylase enzymatic inhibition and antitumor potential of Oxametacin, molecular docking, molecular dynamic simulation and in vitro activity assay processes were performed in the present study. Methods: In the docking study, multiple π - π stacking and H-bond interactions were discovered to play significant roles in the Oxametacin-HDAC3 bindings. Results: Such interactions were proved to be stable by the molecular dynamic simulation. Enzymatic inhibition assay showed potent inhibitory activity of Oxametacin (IC50 value of 0.18 µM) against Hela cell nucleus extract compared with SAHA (0.21 µM). Conclusion: In the isoform selectivity assay, Oxametacin exhibited selectivity for HDAC3 (0.13 µM) over HDAC6 (0.46 µM). In the antiproliferative test, Oxametacin exhibited leukemic cell lines selectivity against the solid tumor cell lines. Current studies reveal that Oxametacin can be used as a lead compound in further development of histone deacetylase inhibitors for the anticancer therapy.

Background: β-cyclodextrin, is a cyclic oligosaccharides bearing seven units of 1, 4-linked glucose units, having distinctive chemical structure i.e. its inner cavity is hydrophobic which facilitates the formation of host-guest complexes with the hydrophobic molecules. Methods: In the present study, we investigated the binding affinities and interactions of different oral anti-diabetic drugs within the cavity of β-cyclodextrin using in silico tool viz. molecular docking simulations for the selection of anti-diabetic drug to develop viable novel drug delivery systems. Results: An understanding of the structural properties of anti-diabetic drugs in relation to predicted docking scores with β-cyclodextrin reveals the suitability of the combination for drug delivery purpose. Among selected anti-diabetic agents, Fasiglifam bearing benzofuran scaffold with –COOH and –SO2 group exhibited maximum MolDock as well as Re-ranks score. Nateglinide demonstrated lowest MolDock score, while Alogliptin and Saxagliptin showed no H-bond interaction with the β- cyclodextrin. Conclusion: The binding conformations of anti-diabetic agents obtained from the present study can be mapped and will be helpful in the selection of polymer for formulation purpose. Furthermore, the results of the present study provide a guideline to select the polymers for the formulation of different therapeutic agents to attain better pharmacological profile with marginal toxicity.

Background: Acquired immunodeficiency syndrome is a disease derive from infection of human immunodeficiency virus, and integrase is an important target for antiviral drugs. Nsubstituted quinolinonyl diketo acid derivatives as integrase strand transfer inhibitors were investigated in this work to discuss the relationships between chemical structures and their bioactivities. Methods: Three-dimensional quantitative structure-activity relationship, pharmacophore, and molecular docking simulations as computational chemistry tools are used in this study. The crystal structure of receptors and ligands from protein data bank are also employed. Results: The structure-activity relationship models with statistically significant parameters are built, and molecular docking simulation is performed to show the rational interaction of the receptor and ligand. Besides, the pharmacophore model generated by four potent integrase inhibitors find the important features which are crucial to the inhibitory activities. Conclusion: In this series of compounds, the modification of hydrophobic and electronegative substituents in benzene ring would be benefit for the inhibitory activity against integrase strand transfer. The hydrophobic interactions and chelating interactions are found in docking simulation result between receptor and ligand, which indicate the importance of diketo acid chain and quinolinonyl moiety. All the results could serve as basis for the development of potential integrase inhibitors.

Introduction: The plants derived component harmine has various pharmacological activities such as antimicrobial, antifungal, antitumor. The antiviral effect of harmine on herpes simplex virus types 1 and 2 (HSV-1 and -2) has been well investigated, while whether it affects BoHV-1 infection is unknown. Objectives: The aim of the study is to investigate whether harmine affects BoHV-1 infection and the virus induced inflammation related signaling MAPK pathways. Methods: To assess the antiviral effect of harmine on BoHV-1 infection, MDBK cells were treated with harmine at different stages of virus infection, including through virus infection stages plus a pretreatment for 1 h, the virus entry stages, postentry stages and the virus binding stags. To evaluate whether the antiviral effects of harmine on BoHV-1 infection was enhanced by the known anti-herpesvirus drug acyclovir (ACV), both harmine and ACY at low concentrations that have minor effects on BoHV-1 infection were selected for combination used for the treatment of MDBK cells. The antiviral effect of the combined chemicals were compared with the application used individually. The effects of harmine on the activation of the inflammation related signaling MAPK pathways were also detected. Results: Here, for the first time we reveals that harmine affects BoHV-1 infection at both early and late stages of infection. The inhibitory effect was significantly enhanced by the known antiherpesvirus medicine ACV. While, it has no apparent effects on the activation of inflammation related signaling of neither p38MAPK nor Erk1/2 stimulated by BoHV-1 infection. Conclusion: Harmine inhibited BoHV-1 replication, in vitro, which could be synergistically enhanced by ACV. But harmine has no evident effect on the inflammation related signaling Erk1/2 and p38MAPK stimulated by BoHV-1 infection.

Background: In this study, 2-(substituted-sulfanyl)-N,N-dicyclohexylacetamide derivatives (2a-2g) and 2-(dicyclohexylamino)-2-oxoethyl-1-substituted carbodithioate derivatives (2h-2m) were synthesized and screened for their antimicrobial activity. Methods: Newly synthesized compounds were screened against two gram negative bacteria (S. typhimurium and E.coli), three gram positive bacteria (S. aureus, B. cereus and L. monocytogenes), four Candida species, four Aspergillus spp. and three Penicillium spp. Among them (2a-2m), compounds 2i (2-(dicyclohexylamino)-2-oxoethyl-thiomorpholine-4-carbodithioate) and 2k (2- (dicyclohexylamino)-2-oxoethyl-4-(4-methoxyphenyl)piperazine-1-carbodithioate) were detected to have higher inhibitory effect than other compounds. Results and Conclusion: Minumum inhibitor concentrations (MICs) of the compounds were determined between the range of 97.5-390 µg/mL. Additionally, parameters determined that some physicochemical and toxic properties were predicted using computational methods.

Background: A series of novel substituted 3-(thiophen-2-yl)pyrazoles was synthesized efficiently and in high yields using simple and convenient procedures starting from 1-phenyl-3- (thiophen-2-yl)-1H-pyrazole-4-carbaldehyde. Methods: The structures of the newly synthesized products were established and their antimicrobial activities were investigated against some bacteria and fungi. Results and Conclusion: The products showed excellent antimicrobial activities against the tested microorganism compared to the standard antibacterial and antifungal drugs.

Background: Glyoxalase-I (Glo-I) enzyme is an attractive new target for developing new cancer therapeutics. This enzyme is a dimeric mononuclear zinc coordinating metalloenzyme, and the core zinc ion was utilized in designing potentially active inhibitors possessing a selective zinc binding feature. Objective: A panel of thiazole based carboxylic acid derivatives were designed, synthesized, and evaluated for their in vitro inhibitory activity against Glo-I enzyme based on their chelating potential with the zinc atom at the core of the active site. Methods: Flexible molecular docking was employed in designing the proposed inhibitors. The designed compounds were synthesized, fully characterized, and in vitro assayed against Glo-I enzyme. Results: Compound 14 was identified as the most potent inhibitor of the series with an IC50 of 2.5 µM. Moreover, the in-silico calculated CDocker scores were in excellent agreement with the experimental inhibitory activity of the compounds. Conclusion: The carboxylic acid group was identified as an indispensable chelating functionality in inhibiting Glo-I enzyme. The data obtained in this study indicate that these compounds could be promising anti-cancer candidates and hence warrant further optimization.

Background: Dihyrdotestosterone (DHT), the most potent circulating androgen hormone, is produced by stereoselective reduction of testosterone (T) under catalysis of NADPH dependent enzyme steroid 5α-reductase (5AR). The DHT production is related to many pathological conditions and endocrine diseases such as Benign Prostatic Hyperplasia (BPH). Many years ago, the use of 5AR inhibitors for the possible control or suppression of DHT formation has become years ago a therapeutic target for the treatment of BPH. During last two decades, several non steroidal and steroidal compounds have been synthesized as reversible and irreversible 5AR inhibitors. Methods: Present study describes the synthesis of 17β-substituted amides of 3-aza-A-homo-4aandrosten- 4-one starting from 16-Dehydropregnelone acetate (16-DPA). The structure of newly synthesized compounds was established on the basis of TLC and various spectroscopic studies and compounds were subjected for their in vitro cytotoxicity studies using prostate cancer cell lines PC-3. Results and Conclusion: Synthesized compounds (13a to 13h) showed better cytotoxicity as compared to reference drug and 3-Aza-A-homo-17β-(4-nitrobenzamido)-4a-androsten-4-one (13b) showed an excellent antiproliferative activity as compared to Dutasteride.