Letters in Drug Design & Discovery - Volume 14, Issue 1, 2017

The recognition of a foreign protein (antigen) by host B and/or T cells and the induction of immune response have a key role for the human immune system. The peptide binding to MHC proteins is a prerequisite for B or T-cell recognition. Determining the peptide-binding preferences exhibited by the MHC extensive set of alleles requires enormous experimental work. A more rational approach is the development of bioinformatics prediction methodologies. Among others, proteochemometrics (PCM) is quite suitable for MHC binding prediction as it simultaneously models the bioactivity of multiple ligands against multiple protein targets. Handling multiple targets is the key to "ligand polypharmacology" and the development of multi-target drugs. The few applications of PCM for MHC binding prediction showed that the developed models have excellent predictive ability

A quantitative structure-activity relationship (QSAR) study has been conducted on a series of oxadiazole and triazole substituted naphthyridines as HIV-1 integrase inhibitors. A multiple linear regression (MLR) analysis showed that the HIV-1 inhibition potency of the compounds was primarily governed by their molecular size and thus there could be dispersion interaction between the inhibitors and the enzyme. Using the MLR model, a few new compounds having the higher potency than the compounds in the existing series of oxadiazole and triazole substituted naphthyridines were predicted. When a docking study was performed on these predicted compounds with the enzyme (PDB id: 1BL3), almost all the compounds were also found to form several hydrogen bonds with the receptor as well as to have some hydrophobic interactions. The most active compound in the series was, however, found to have slightly different interactions and these different interactions were probably the reason for its better activity. Our predicted compounds were also found to have much higher potency than the FDA approved two compounds, raltegravir and elvitegravir

Targeting of MMP-9 could be a useful approach for anticancer therapy. The inhibitory activities of 23 flavonoids on tumor necrosis factors alpha (TNFα)-induced matrix metalloproteinases 9 (MMP-9) gene expression were analyzed quantitatively. To elucidate the relationships between the structural properties of flavonoids and their inhibitory activities, comparative molecular field analysis and comparative molecular similarity indices analysis were carried out. The structural conditions required for high inhibitory activity towards TNFα-induced MMP-9 gene expression were derived. In addition, for spiraeoside, which showed the best activity among the test compounds, reverse transcription polymerase chain reaction (PCR), real-time PCR analysis, and promoter-reporter assay were performed. Spiraeoside could be a lead compound for the anticancer agents.

The Src Homology 2 (SH2) domain of Stat3, which acts as therapeutic target, are used to treat multiple myeloma (MM). The activities of Tolyl-N-alkyl derivatives as Stat3 inhibitors were analyzed, using the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking method. The final CoMFA and CoMSIA models yielded statistically significant results with the cross-validated correlation coefficients q2 of 0.566 and 0.644, the correlation coefficients r2 of 0.945 and 0.967, respectively. In addition, we used the CoMFA and CoMSIA models to design a series of new inhibitors. Molecular docking explored the binding mode between the receptor protein and the ligand. The docking results demonstrated that the key amino acid residues (Lys626, Gln635, Ser636, Glu625, Trp623, Glu638 and Tyr657) were found in binding site. The ligand was located in the hydrophobic binding region formed by the amino acid residues: Val637, Phe716, Pro715, Ile659, Tyr640 and Pro639. The obtained information from computational studies can offer a good guideline for designing novel Stat3 inhibitors.

Bromodomains (BRDs) are important protein domains in the reading process of epigenetic marks. Recent studies have demonstrated that human BET protein BRD4 which contains bromodomains plays a critical role in cell proliferation, cancer growth and virus-host pathogenesis. In this work, a chemical-core substitution strategy was employed to identify BRD4 bromodomain inhibitors that had new and different chemical cores featuring common chemical portions with the parent fragments. After the combination of compounds BI2536 and GSK726, two hit compounds 6h and 6i represented potent lead compounds to deserve further optimization. Then, ten analogous compounds were synthesized and evaluated by in-vitro biological test. Among them, compound 6d exhibited the greatest inhibition against BRD4 bromodomains with IC50 value of 180 nM.

In this work, a series of derivatives containing 1,2,3-triazole and isoxazole were synthesized. All of them were evaluated as novel dual AChE inhibitors. Most of synthesized compounds showed moderate to good inhibitory potency toward AChE. Among them, N-((1-(4-methylbenzyl)- 1H-1,2,3-triazol-4-yl)methyl)-5-(p-tolyl)isoxazole-3-carboxamide (5m) was the most potent AChE inhibitor, being 12-fold more potent than rivastigmine, as the reference drug. Also, molecular modeling revealed that compound 5m targeted both the catalytic anionic site (CAS) and the peripheral anionic site (PAS) of AChE.

The physiological effects of glucagon like peptide-1 (GLP-1) are of great interest because of the potential clinical relevance of this peptide. In the pancreas, GLP-1 is believed to enhance insulin secretion through mechanism involving the regulation of ion channels for manipulating in vivo survival of GLP-1, two separate approaches can be seen-the development of analogs of GLP-1 or the use of selective enzyme inhibitors DPP-IV inhibition is a viable approach to treating diabetes. We have screened a vast library of compound and found ten best compounds with potent drug like activity using virtual screening and docking methods. The best molecule was validated by molecular dynamic simulation method. Type 2 diabetes mellitus is caused mainly due to an imbalance in the relationship between glucagon like peptide-1 and insulin levels in plasma. Glucagon exerts its action through activation of the glucagon receptor DPP-IV. These observations have prompted interest in blockade of DPP-IV activity for the control of over production of hepatic glucose or the treatment of type 2 diabetes mellitus. In the present study, a large virtual library of compounds was screened against the crystal structure of DPP-IV to identify a favorable therapeutic choice of DPP-IV antagonist. The interactions of lead compound with the ligand binding residues of DPP-IV were analyzed. The proposed lead compound was also compared with some marketed preparation DPP-IV antagonists for their binding affinity and other pharmacological properties. As a conclusion of this study, we have identified a compound ZINC05998557 (6) as potent DPP-IV antagonist for the treatment of type 2 diabetes mellitus.

Background: Lipoxygenases(LOXs) are a family of enzymes which catalyze the oxidation of unsaturated fatty acids. Objective: To quantitatively disclose the relationship between activity and structure of a series of 12- LOX inhibitors. Method: 3D-QSAR (three dimensions quantitative structure-activity relationship) studies based on COMFA(comparative molecular field analysis) and COMSIA(comparative molecular similarity indices analysis) and pharmacophore studies were performed. Results: 3D-QSAR results show that both CoMFA and CoMSIA models yielded well statistical significance respectively, with q2=0.708, r2=0.983, F=162.3, SEE=0.090 in CoMFA model and q2=0.735, r2=0.981, F=130.5, SEE=0.095 in CoMSIA model, four derivatives as potential 12-LOX inhibitors with high predicted bioactivities has been designed. Additionally, pharmacophore results suggested different group on the core parts of 12-LOX inhibitor might enhance the bioactivities.

Quantitative structure-activity relationship (QSAR) and docking studies have been performed on a large series of cinnamic acid analogues studied by various authors as Epidermal Growth Factor Receptor (EGFR) inhibitors. A multiple linear regression (MLR) analysis has shown that electronic properties of these compounds are the governing factors of their activity and docking study has shown that compounds can form hydrogen bonds with the receptor and have effective steric interactions involving dispersion forces. Using the MLR model, some new compounds were proposed that have higher potency than the existing ones.

Overexpression of antiapoptotic Bcl-2 family proteins plays an important role in tumor maintenance, progression, and chemo-resistance. Targeting these antiapoptotic proteins using nonpeptidic small molecule inhibitors is a new and appealing strategy for cancer therapy. In this study, a novel apogossypolone (ApoG2) derivative, 6, 7, 6', 7'- tetrahydroxy -3, 3'- dimethyl - [2, 2'] binaphthalenyl- 1, 4, 1', 4'- tetraone (compound 6) was synthesized and screened in vitro for its biological activities. Using the MTT assay and colony formation assay, we found that ApoG2 exerted more potent cytotoxic activities against PC-3 and MDA-231 cells in a dose-dependent manner than the compound 6. In addition, Hoechst 33258 assay results further revealed that ApoG2 exhibits obvious apoptotic characteristics in a dose-dependent manner, but the compound 6 led to apoptosis with less extent. Taken together, albeit the compound 6 inferior to ApoG2 in many ways on cancer cells in vitro, our results suggest that the compound 6 still represents a candidate drug for the development of novel apoptosis-based therapies for cancer.

In continuation of our study on anticancer compounds, a series of novel artemisinin dimers have been synthesized and evaluated for their cytotoxic effects against three human cancer cell lines, including HepG2 (liver cancer), MCF-7(breast cancer) and HL-60 (leukemia cancer). The assay results showed that most of the compounds displayed inhibitory effects against all three human cancer cell lines tested, and seemed to be more cytotoxic toward the blood cancer cells (HL-60) than liver (HepG2), and breast (MCF-7) cancer cells. Among the synthesized artemisinin dimers, the compound 10d with a double bond bridge exhibited the most potent cytotoxicity with IC50 values of 5.08, 4.82 and 1.32 μg/mL against the HepG2, MCF-7, and HL-60 cell lines, respectively.

Background: Ovarian cancer is the ninth most common cancer. Microarray technology could analyze genes differentially expressed during cancer progression. Purpose: To analyze the molecular mechanisms of the development in ovarian cancer and screen potential therapeutic targets. Methods: GSE37582 was downloaded from Gene Expression Omnibus database. The dataset contained 121 lymphoblastoid cell lines (LCLs) from 74 ovarian cancer patients and 47 cancer-free controls. Lymphocytes isolated from blood samples of each patient and control were used to establish LCLs via EBV transformation. The differentially expressed genes (DEGs) were identified by LIMMA package, followed by functional enrichment analysis. TRANSFAC database was utilized to select transcription factors (TFs) and construct a transcriptional regulatory network. Networked Gene Prioritizer method was performed to prioritize cancer-associated regulatory subnets. Results: Totally, 131 up- and 112 down- regulated genes were screened in ovarian cancer, which were enriched in several processes such as response to protein stimulus, and anti-apoptosis. A transcriptional regulatory network was constructed including 2630 nodes and 5462 interactions. HSF1 (heat shock transcription factor 1), E2F2 (E2F transcription factor 2), EGR1 (early growth response 1) and ETV4 (ets variant 4) were identified as differentially expressed TFs. Three transcriptional regulatory subnets were obtained as candidate subnets, based on which RPL26 and MST1 were regulated by MYC and DUSP1 was regulated by USF1. Conclusion: The differentially expressed TF, HSF1, and regulatory interactions of MYCRPL26/ MST1 and USF1-DUSP1 might play critical roles in ovarian cancer progression and these molecules could provide theoretical bases for further researches on ovarian cancer treatment.

Background: Alpinia nigra is a well-known ethnomedicinally important plant used to treat many diseases in the folks. Objective: It has been investigated for its antileshmanial activity in this study. Method: Mature aromatic seeds were subjected to organic solvent (n-hexane, ethylaceate and methanol) extraction. All the extracts were tested against Leishmania donovoni promastigotes in vitro. The active extracts were subjected to column chromatography for further separation and purification of compounds. The purified compounds were characterized by standard spectroscopic techniques and tested against the promastigotes. Results: Two of the extracts along with the purified compound A and B were found significantly active against the leishmania promastigotes. MTT assay revealed remarkable leshmanicidal efficacy of compound A (IC50 – 63.0 nM) and B (IC50 - 90.5 nM) against the promastigotes. Human red blood cells hemolysis experiment suggests both the compounds to be fairly safe. Conclusion: These diterpene compounds could be used as potential hit molecules for further drug development against Leishmaniasis. This is the first report of antileshmanial activities of two isolated labdane diterpenes from A. nigra.