Identification of sulfonamide based butyrylcholinesterase inhibitors through scaffold hopping approach.

Butyrylcholinesterase (BChE), a hydrolytic enzyme, is responsible for the termination of the action of acetylcholine besides acetylcholinesterase (AChE) in the synaptic cleft of the brain. The alteration in the enzyme level, in patients with the progression of Alzheimer's disease, makes it a therapeutic target. In the present study, we developed BChE inhibitors through scaffold hopping by exploring two previously reported compounds, i.e., 1,4-bis((4-chlorophenyl) sulfonyl)-3,6-diphenylpiperazine-2,5-dione and N-(2-chlorophenyl)-4-(phenylsulfonamido)benzamide, to afford scaffold and pharmacophore fragments, respectively. The N,2-diphenyl-2-(phenylsulfonamido)acetamide derivatives, thus designed, were synthesised and screened for the inhibition of AChE and BChE enzymes. Compounds 30 and 33 were found to be most active against BChE among the derivatives, with IC50 values of 7.331 ± 0.946 and 10.964 ± 0.936 µM, respectively. The compounds displayed a non-competitive mode of inhibition along with BBB permeability and good cell viability on SH-SY5Y cell line. The molecular docking analysis of the compounds with BChE showed interactions with Trp82, Trp231, Leu286, and His438. The molecular dynamics study revealed the stability of the protein-ligand complexes.

Development of homology model, docking protocol and Machine-Learning based scoring functions for identification of Equus caballus's butyrylcholinesterase inhibitors.

Machine learning (ML), an emerging field in drug design, has the potential to predict in silico toxicity, shape-based analysis of inhibitors, scoring function (SF) etc. In the present study, a homology model, docking protocol, and a dedicated SF have been developed to identify the inhibitors of horse butyrylcholinesterase (BChE) enzyme. Horse BChE enzyme has homology with human BChE and is a substitute for the screening of in vitro inhibitors. The developed homology model was validated and the active site residues were identified from Cavityplus to generate grid box for docking. The validation of docking involved comparison of interactions of ligands co-crystallised with human BChE and the docked poses of the corresponding ligands with horse BChE. A high degree of similarity in the interaction profiles of generated poses validated the docking protocol. Scoring of ligands was further validated by docking with known BChE inhibitors. The binding energies obtained from SF was correlated with IC50 values of inhibitors through classification and regression-based methods, which indicated poor predictivity of native SF. Therefore, protein-ligand binding energy, interaction profile, and ligand descriptors were used to develop and validate the classification and regression-based models. The validated extra tree binary classifier, random forest and extra tree regression-based models were compiled as a protein-ligand SF and were made available to the users through web application and python library. ML models exhibited improved area under the curve for ROC and good correlation between the predicted and observed IC50 values, than the Autodock SF. Communicated by Ramaswamy H. Sarma.

Correlation of subendometrial-endometrial blood flow assessment by two-dimensional power Doppler with pregnancy outcome in frozen-thawed embryo transfer cycles.

CONTEXT: Various markers have been proposed to evaluate endometrial receptivity, such as molecular markers and sonographic markers. Commonly used sonographic markers include endometrial thickness and pattern. A good endometrial blood flow is considered necessary for improved pregnancy outcome. AIM: The aim of the present study is to evaluate the role of subendometrial endometrial blood flow with two-dimensional-power Doppler (2D-PD) in predicting pregnancy outcome in hormone replacement frozen-thawed embryo transfer (FET) cycles. SETTING AND DESIGN: Prospective, non-randomized observational study. A total of 165 patients undergoing their first FET cycle were evaluated for subendometrial-endometrial blood flow by 2D-PD once the endometrium was ≥7 mm thick. Group A consisted of 127 women showing the presence of subendometrial-endometrial blood flow. Group B comprised of 38 women in whom subendometrial blood flow was absent. Progesterone supplement was added and transfer of 2-3 cleavage stage good quality embryos was done after 3 days. STATISTICAL ANALYSIS: Independent two-tailed t-test and Chi-square test. RESULTS: There was no significant difference in body mass index, endometrial thickness, follicle stimulating hormone, luteinizing hormone levels, number of mature oocytes, semen parameters and the number of good quality embryos in the two groups (P > 0.05). The mean age in Group A was 32.05 years and 33.73 years in Group B, and the difference was statistically significant (P = 0.04). Overall pregnancy rate (PR) was 30.90%. PRs were significantly higher in the presence of subendometrial-endometrial blood flow than in its absence (35.43% vs. 15.78%, P = 0.02). Furthermore, clinical pregnancy rate and implantation rate were significantly higher in Group A when compared to Group B (31.49% and 14.79% vs. 13.15% and 6.52%, P = 0.02 and 0.03, respectively). CONCLUSION: The presence of endometrial blood flow significantly improves cycle outcome in hormone replacement therapy-FET cycles.

Drug repositioning for orphan diseases.

The need and opportunity to discover therapeutics for rare or orphan diseases are enormous. Due to limited prevalence and/or commercial potential, of the approximately 6000 orphan diseases (defined by the FDA Orphan Drug Act as <200 000 US prevalence), only a small fraction (5%) is of interest to the biopharmaceutical industry. The fact that drug development is complicated, time-consuming and expensive with extremely low success rates only adds to the low rate of therapeutics available for orphan diseases. An alternative and efficient strategy to boost the discovery of orphan disease therapeutics is to find connections between an existing drug product and orphan disease. Drug Repositioning or Drug Repurposing--finding a new indication for a drug--is one way to maximize the potential of a drug. The advantages of this approach are manifold, but rational drug repositioning for orphan diseases is not trivial and poses several formidable challenges--pharmacologically and computationally. Most of the repositioned drugs currently in the market are the result of serendipity. One reason the connection between drug candidates and their potential new applications are not identified in an earlier or more systematic fashion is that the underlying mechanism 'connecting' them is either very intricate and unknown or indirect or dispersed and buried in an ever-increasing sea of information, much of which is emerging only recently and therefore is not well organized. In this study, we will review some of these issues and the current methodologies adopted or proposed to overcome them and translate chemical and biological discoveries into safe and effective orphan disease therapeutics.

Integrative systems biology approaches to identify and prioritize disease and drug candidate genes.

Although a number of computational approaches have been developed to integrate data from multiple sources for the purpose of predicting or prioritizing candidate disease genes, relatively few of them focus on identifying or ranking drug targets. To address this deficit, we have developed an approach to specifically identify and prioritize disease and drug candidate genes. In this chapter, we demonstrate the applicability of integrative systems-biology-based approaches to identify potential drug targets and candidate genes by employing information extracted from public databases. We illustrate the method in detail using examples of two neurodegenerative diseases (Alzheimer's and Parkinson's) and one neuropsychiatric disease (Schizophrenia).

PhenoHM: human-mouse comparative phenome-genome server.

PhenoHM is a human-mouse comparative phenome-genome server that facilitates cross-species identification of genes associated with orthologous phenotypes (http://phenome.cchmc.org; full open access, login not required). Combining and extrapolating the knowledge about the roles of individual gene functions in the determination of phenotype across multiple organisms improves our understanding of gene function in normal and perturbed states and offers the opportunity to complement biologically the rapidly expanding strategies in comparative genomics. The Mammalian Phenotype Ontology (MPO), a structured vocabulary of phenotype terms that leverages observations encompassing the consequences of mouse gene knockout studies, is a principal component of mouse phenotype knowledge source. On the other hand, the Unified Medical Language System (UMLS) is a composite collection of various human-centered biomedical terminologies. In the present study, we mapped terms reciprocally from the MPO to human disease concepts such as clinical findings from the UMLS and clinical phenotypes from the Online Mendelian Inheritance in Man knowledgebase. By cross-mapping mouse-human phenotype terms, extracting implicated genes and extrapolating phenotype-gene associations between species PhenoHM provides a resource that enables rapid identification of genes that trigger similar outcomes in human and mouse and facilitates identification of potentially novel disease causal genes. The PhenoHM server can be accessed freely at http://phenome.cchmc.org.

Thyroid hormones in pregnancy and preeclampsia.

OBJECTIVE: There is a state of hypothyroxinemia in normal pregnancy and in preeclampsia, when biochemically raised TSH occurs. Identification of changes in thyroid hormones in preeclampsia might be of help in preventing the occurrence of preeclampsia. MATERIAL AND METHODS: The present study was carried out in a hundred women with preeclampsia, 100 age- and parity matched normotensive pregnant women and 50 age-matched healthy non-pregnant women. Thyroid hormones [total T3,T4 and TSH], serum albumin and uric acid were analyzed in these subjects. RESULTS: Women with preeclampsia had higher TT3, TT4 levels as compared to non pregnant women [p<0.05], but preeclamptic TT3, TT4 levels were lower compared to normotensive pregnant women [p<0.05, p<0.01]. TSH levels were higher in both preeclamptic & normotensive pregnant women compared to nonpregnant women [p<0.001] and levels were lower in normotensive pregnant women as compared to nonpregnant women [p<0.001]. A significant negative correlation was observed between birth weight and TSH levels [r=-0.296, p<0.001] serum albumin and TSH levels in preeclamptic women [r=-0.781, p<0.01]. Also, a significant positive correlation was observed between birth weight and albumin [r=0.298, p<0.001]; birth weight and serum uric acid levels [r=-0.46, p<0.01], and serum albumin and TT3 & TT4 levels [r=0.409 & r=0.35, p<0.01 respectively]. CONCLUSION: These findings indicate that there is state of hypothyroxinemia in normal pregnancy and in preeclampsia. Identification of changes in thyroid hormones in preeclampsia might be of help in preventing the occurrence of preeclampsia.