Quantitative structure–activity relationship (QSAR) studies as strategic approach in drug discovery

Drug design is a process which is driven by technological breakthroughs implying advanced experimental and computational methods. Nowadays, the techniques or the drug design methods are of paramount importance for prediction of biological profile, identification of hits, generation of leads, and moreover to accelerate the optimization of leads into drug candidates. Quantitative structure–activity relationship (QSAR) has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. From decades to recent research, QSAR methods have been applied in the development of relationship between properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. Classical QSAR studies include ligands with their binding sites, inhibition constants, rate constants, and other biological end points, in addition molecular to properties such as lipophilicity, polarizability, electronic, and steric properties or with certain structural features. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free–Wilson approaches, which exploit the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, and ANN. This paper provides an overview of 1-6 dimension-based developed QSAR methods and their approaches. In particular, we present various dimensional QSAR approaches, such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis, Topomer CoMFA, self-organizing molecular field analysis, comparative molecule/pseudo receptor interaction analysis, comparative molecular active site analysis, and FLUFF-BALL, 4D-QSAR, and G-QSAR approaches.     

3,4-Disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thiones: synthesis, antimicrobial evaluation and QSAR investigations using Hansch analysis

The 3,4-disubstituted-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione derivatives were synthesized and characterized by physicochemical and spectral means, and the results of antimicrobial study of these compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans by tube dilution method indicated that 4-(4-chlorophenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 6 and 4-(4-fluorophenyl)-3-(4-nitrophenylsulfonyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2-thione 12 were the most potential ones. Further, the QSAR studies by Hansch analysis applied to find out the correlation between physicochemical characteristics of synthesized compounds with antimicrobial activity demonstrated the contribution of electronic parameter, total energy (Te) and the topological parameter (valence second order molecular connectivity index (2 chi v). Excellent statistically significant models were developed by Hansch approach (r2 = 0.828-0.898) for the three microorganisms under study. The cross-validated r2 (q2), which is an indication of the predictive capability of the model for all cases was also very good (q2 = 0.776-0.875).     

Environmental Monitoring and Health Risk Assessment of African Catfish Clarias gariepinus (Burchell, 1822) Cultured in Rural Ponds, India

Water quality monitoring of Clarias gariepinus culture ponds (n?=?27) revealed poor physico-chemical conditions and metal contaminants in fish tissues (n?=?324). Human health risk assessment for some heavy metal contamination delineated low risk in general except for Aluminium (Al), Iron (Fe) and Lead (Pb) which accumulated significantly (p?<?0.05) high in tissues. Health risks values were 6.3?×?10^?3–9.6?×?10^?3 for Al; 3?×?10^?3–9.7?×?10^?3 for Fe and 1.15?×?10^?5–9.3?×?10^?6 for Pb respectively suggesting that contamination of Pb particularly in ponds fed with chicken waste (CW) was posing high risks.     

Barriers to using skilled birth attendants’ services in mid- and far-western Nepal: a cross-sectional study

Background

Skilled birth attendants (SBAs) provide important interventions that improve maternal and neonatal health and reduce maternal and neonatal mortality. However, utilization and coverage of services by SBAs remain poor, especially in rural and remote areas of Nepal. This study examined the characteristics associated with utilization of SBA services in mid- and far-western Nepal.

Methods

This cross-sectional study examined three rural and remote districts of mid- and far-western Nepal (i.e., Kanchanpur, Dailekh and Bajhang), representing three ecological zones (southern plains [Tarai], hill and mountain, respectively) with low utilization of services by SBAs. Enumerators assisted a total of 2,481 women. All respondents had delivered a baby within the past 12 months. We used bivariate and multivariate analyses to assess the association between antenatal and delivery care visits and the women’s background characteristics.

Results

Fifty-seven percent of study participants had completed at least four antenatal care visits and 48% delivered their babies with the assistance of SBAs. Knowing the danger signs of pregnancy and delivery (e.g., premature labor, prolonged labor, breech delivery, postpartum hemorrhage, severe headache) associated positively with four or more antenatal care visits (OR?=?1.71; 95% CI: 1.41-2.07). Living less than 30 min from a health facility associated positively with increased use of both antenatal care (OR?=?1.44; 95% CI: 1.18-1.77) and delivery services (OR?=?1.25; CI: 1.03-1.52). Four or more antenatal care visits was a determining factor for the utilization of SBAs.

Conclusions

Less than half of the women in our study delivered babies with the aid of SBAs, indicating a need to increase utilization of such services in rural and remote areas of Nepal. Distance from health facilities and inadequate transportation pose major barriers to the utilization of SBAs. Providing women with transportation funds before they go to a facility for delivery and managing transportation options will increase service utilization. Moreover, SBA utilization associates positively with women’s knowledge of pregnancy danger signs, wealth quintile, and completed antenatal care visits. Nepal’s health system must develop strategies that generate demand for SBAs and also reduce financial, geographic and cultural barriers to such services.

     

Geographic variations in clinical presentation and outcomes of decompressive surgery in patients with symptomatic degenerative cervical myelopathy: analysis of a prospective,international multicenter cohort study of 757 patients

Background Context

Degenerative cervical myelopathy (DCM) is a progressive degenerative spine disease and the most common cause of spinal cord impairment in adults worldwide. Few studies have reported on regional variations in demographics, clinical presentation, disease causation, and surgical effectiveness.

Characterization of a new SNP c767A/T (Arg222Trp) in the candidate TSG FUS2 on human chromosome 3p21.3: prevalence in Asian populations and analysis of association with nasopharyngeal cancer

The FUS2 gene, encoding a novel cytoplasmic acetyltransferase, resides in the tumor suppressor gene region on human chromosome 3p21.3 and is considered a promising candidate tumor suppressor gene. We have identified a new single nucleotide polymorphism (SNP), c767A/T, in the coding region of the gene. The polymorphism leads to a non-conservative amino acid change (R222W) located between the acetyltransferase (GNAT) and the proline-rich domains of the protein. We have analyzed 254 subjects included in 14 sub-populations. The occurrence of the SNP varies with the ethnicity of the population, suggesting that this SNP could be a valuable biomarker for population genetics. It is most prevalent in various Asian populations (T allele frequency>0.54), followed by the Canadian polar Inuit (T allele frequency=0.3), African American (T allele frequency=0.17), and Caucasian population (T allele frequency=0.1). Since nasopharyngeal carcinoma (NPC) is frequent in Southern China, Taiwan, Borneo and polar Canada, we further tested for the possible association of the FUS2 SNP with this form of endemic cancer. Our analysis, albeit limited, suggests no likely association between NPC and the FUS2 gene polymorphism. Further large-scale case-control studies are necessary and warranted to prove the strength of this contention.     

Endoscopic jejunal biopsy culture: a simple and effective method to study jejunal microflora

Background  

Jejunal fluid culture is the gold standard for assessing jejunal microflora. Aspiration of jejunal fluid is sometime difficult. As the microorganisms rests on the mucosal surface, culture of the mucosal biopsy may be a possible alternative method.     

Amyloid histology stain for rapid bacterial endospore imaging

Bacterial endospores are some of the most resilient forms of life known to us, with their persistent survival capability resulting from a complex and effective structural organization. The outer membrane of endospores is surrounded by the densely packed endospore coat and exosporium, containing amyloid or amyloid-like proteins. In fact, it is the impenetrable composition of the endospore coat and the exosporium that makes staining methodologies for endospore detection complex and challenging. Therefore, a plausible strategy for facile and expedient staining would be to target components of the protective surface layers of the endospores. Instead of targeting endogenous markers encapsulated in the spores, here we demonstrated staining of these dormant life entities that targets the amyloid domains, i.e., the very surface components that make the coats of these species impenetrable. Using an amyloid staining dye, thioflavin T (ThT), we examined this strategy. A short incubation of bacillus endospore suspensions with ThT, under ambient conditions, resulted in (i) an enhancement of the fluorescence of ThT and (ii) the accumulation of ThT in the endospores, affording fluorescence images with excellent contrast ratios. Fluorescence images revealed that ThT tends to accumulate in the surface regions of the endospores. The observed fluorescence enhancement and dye accumulation, coupled with the sensitivity of emission techniques, provide an effective and rapid means of staining endospores without the inconvenience of pre- or posttreatment of samples.     

Regression of prostate cancer xenografts by RLIP76 depletion

RLIP76 plays a central role in radiation and chemotherapy resistance through its activity as a multi-specific ATP-dependent transporter which is over-expressed in a number of types of cancers. RLIP76 appears to be necessary for cancer cell survival because both in vitro cell culture and in vivo animal tumor studies show that depletion or inhibition of RLIP76 causes selective toxicity in malignant cells. RLIP76 induces apoptosis in cancer cells through the accumulation of endogenously formed GS-E. The results of our in vivo studies demonstrate that administration of RLIP76 antibodies, siRNA or anti-sense to mice bearing xenografts of PC-3 prostate cancer cells leads to near complete regression of established subcutaneous xenografts with no apparent toxic effects. Since anti-RLIP76 IgG (which inhibit RLIP76-mediated transport), siRNA and antisense (which deplete RLIP76) showed similar tumor regressing activities, our results indicate that the inhibition of RLIP76 transport activity at the cell surface is sufficient for observed anti-tumor activity. These studies indicate that RLIP76 serves a key effector function for the survival of prostate cancer cells and that it is a valid target for cancer therapy.