Combinatorial Chemistry & High Throughput Screening - Volume 22, Issue 8, 2019

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

Objective: Prostaglandin 2 (PGD2) mediated signalling of Chemoattractant Receptorhomologous molecule expressed on Th2 cells (CRTh2) receptor has been implicated in the recruitment of inflammatory cells. This explains the design of highly selective compounds with innate abilities to antagonize PGD2-CRTh2 interactions and prevent pro-inflammatory allergies such as rhinitis and uncontrolled asthma. The development of PGD2-competitive CRTh2 binders; CAY10471 and Fevipiprant represent remarkable therapeutic progress even though they elicit disparate pharmacological propensities despite utilizing the same binding pocket. Methods & Results: In this study, we seek to pinpoint the underlying phenomenon associated with differential CRTh2 therapeutic inhibition by CAY10471 and Fevipiprant using membraneembedded molecular dynamics simulation. Findings revealed that the common carboxylate group of both compounds elicited strong attractive charges with active site Arg170 and Lys210. Interestingly, a distinctive feature was the steady occurrence of high-affinity salt-bridges and an Arg170-mediated pi-cation interaction with the tetrahydrocarbozole ring of CAY10471. Further investigations into the active site motions of both ligands revealed that CAY10471 was relatively more stable. Comparative binding analyses also revealed that CAY10471 exhibited higher ΔG, indicating the cruciality of the ring stabilization role mediated by Arg170. Moreover, conformational analyses revealed that the inhibitory activity of CAY10471 was more prominent on CRTh2 compared to Fevipiprant. Conclusions: These findings could further advance the strategic design of novel CRTh2 binders in the treatment of diseases related to pro-inflammatory allergies.

Aim and Objective: It is interesting to find the gene signatures of cancer stages based on the omics data. The aim of study was to evaluate and to enrich the array data using gene ontology and ncRNA databases in colorectal cancer. Methods: The human colorectal cancer data were obtained from the GEO databank. The downregulated and up-regulated genes were identified after scoring, weighing and merging of the gene data. The clusters with high-score edges were determined from gene networks. The miRNAs related to the gene clusters were identified and enriched. Furthermore, the long non-coding RNA (lncRNA) networks were predicted with a central core for miRNAs. Results: Based on cluster enrichment, genes related to peptide receptor activity (1.26E-08), LBD domain binding (3.71E-07), rRNA processing (2.61E-34), chemokine (4.58E-19), peptide receptor (1.16E-19) and ECM organization (3.82E-16) were found. Furthermore, the clusters related to the non-coding RNAs, including hsa-miR-27b-5p, hsa-miR-155-5p, hsa-miR-125b-5p, hsa-miR-21-5p, hsa-miR-30e-5p, hsa-miR-588, hsa-miR-29-3p, LINC01234, LINC01029, LINC00917, LINC00668 and CASC11 were found. Conclusion: The comprehensive bioinformatics analyses provided the gene networks related to some non-coding RNAs that might help in understanding the molecular mechanisms in CRC.

Aim and Objective: The stability of the G-quadruplex structure can increase its activity in telomerase inhibiting cancer cells. In this study, a molecular dynamics simulation method was used to study the effect of three phenanthroline-based ligands on the structure of G-quadruplex at the temperatures of 20, 40, 60 and 80°C. Materials and Methods: RMSD values and frequency of calculated RMSD in the presence and absence of ligands show that ligands cause the relative stability of the G-quadruplex, particularly at low temperatures. The calculation of hydrogen bonds in Guanine-tetrads in three different quadruplex sheets shows that the effect of ligands on the sheets is not the same so that the bottom sheet of G-quadruplex is most affected by the ligands at high temperatures, and the Guaninetetrads in this sheet are far away. Conformation factor was calculated as a measure of ligands binding affinity for each of the G-quadruplex residues. Results: The results show that the studied ligands interact more with the G-quadruplex than loop areas, although with increasing temperature, the binding area also includes the G-quadruplex sheets. The contribution of each of the residues involved in the G-quadruplex binding area with ligands was also calculated. Conclusion: The calculations performed are consistent with the previous experimental observations that can help to understand the molecular mechanism of the interaction of phenanthroline and its derivatives with quadruplex.

Background: The Soluble Epoxide Hydrolase (sEH) is a ubiquitously expressed enzyme in various tissues. The inhibition of the sEH has shown promising results to treat hypertension, alleviate pain and inflammation. Objective: In this study, the power of machine learning has been employed to develop a predictive QSAR model for a large set of sEH inhibitors. Methods: In this study, the random forest method was employed to make a valid model for the prediction of sEH inhibition. Besides, two new methods (Treeinterpreter python package and LIME, Local Interpretable Model-agnostic Explanations) have been exploited to explain and interpret the model. Results: The performance metrics of the model were as follows: R2=0.831, Q2=0.565, RMSE=0.552 and R2 pred=0.595. The model also demonstrated good predictability on the two extra external test sets at least in terms of ranking. The Spearman’s rank correlation coefficients for external test set 1 and 2 were 0.872 and 0.673, respectively. The external test set 2 was a diverse one compared to the training set. Therefore, the model could be used for virtual screening to enrich potential sEH inhibitors among a diverse compound library. Conclusion: As the model was solely developed based on a set of simple fragmental descriptors, the model was explained by two local interpretation algorithms, and this could guide medicinal chemists to design new sEH inhibitors. Moreover, the most important general descriptors (fragments) suggested by the model were consistent with the available crystallographic data. The model is available as an executable binary at http://www.pharm-sbg.com and https://github.com/shamsaraj.

Background: Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both. Aim and Objective: The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities. Materials and Methods: Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups. Results: The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site. Conclusion: It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.

Aim and Objective: Ischemia modified albumin (IMA) is a biomarker that has been introduced recently for use in the evaluation of oxidative stress. The aim of this study was to measure the ischemia modified albumin serum levels in pediatric patients with diabetic ketoacidosis (DKA) during acidosis and after the patient recovered from acidosis and to compare these with the control group. Materials and Methods: Pediatric patients with Type I diabetes mellitus (T1DM) who were admitted to the pediatric intensive care unit with the diabetic ketoacidosis were assigned as the study group and healthy children who were admitted to the outpatient clinic and decided as healthy after clinic and laboratory evaluation were selected as the control group. IMA and adjusted IMA levels were evaluated in the blood samples from the control group and the study group when admitted first time to the intensive care unit during the acidosis period (DKA before treatment, DKA-BT), and after recovering from acidosis (DKA after treatment, DKA-AT). Results: A total of 24 pediatric patients with diabetic ketoacidosis and 30 healthy control children matching age and sex were included in the current study. The albumin levels in pediatric patients with T1DM during DKA-BT were higher than the albumin levels after acidosis (4.101±0.373, 3.854±0.369 g/dL, respectively) (p<0.05). However, there was no significant difference when these values were compared to the control group. Mean values of IMA and Adj-IMA were statistically higher in DKAAT compared to the control group (0.748±0.150 vs 0.591±0.099, p< 0.001; 0.708±0.125 vs 0.607±0.824, p< 0.001, respectively). IMA and adjusted IMA levels measured after recovered from acidosis were significantly higher compared to the level of IMA during DKA (0.748±0.150 vs 0.606±0.105 as absorbance unit, p<0.001; 0.708±0.125 vs 0.625±0.100, p<0.05, respectively). Conclusion: In children with T1DM, even though acidosis recovered following the treatment in diabetic ketoacidosis, which is an oxidative stress marker, the ischemia modified albumin levels and adjusted ischemia modified albumin levels were high.