Descriptor-free QSAR: effectiveness in screening for putative inhibitors of FGFR1.

The long short-term memory (LSTM) algorithm has provided solutions to the limitations of the descriptors-utilizing QSAR models in drug design. However, the direct application of LSTM remains scarce. The effectiveness of a descriptor-free QSAR (LSTM-SM) in modeling the FGFR1 inhibitors dataset while comparing with two conventional QSAR using descriptors (126 bits Morgan fingerprint and 2 D descriptors respectively) as a baseline model was investigated in this study. The validated descriptor-free QSAR model was thereafter used to screen for active FGFR1 inhibitors in the ChemDiv database and subjected to molecular docking, induced-fit docking, QM-MM optimization, and molecular dynamics simulations to filter for compounds with high binding affinity and suggest the putative mechanism of inhibition and specificity. The LSTM-SM model performed better than conventional QSAR; having accuracy, specificity, and sensitivity of 0.92, model loss of 0.025, and AUC of 0.95. Fifteen thousand compounds were predicted as actives from the ChemDiv database and four compounds were finally selected. Of the four, two showed putatively effective binding interactions with key active site residues. Molecular dynamics simulations on these compounds in complex with the receptor further give insight into the conformational dynamics of each compound bounded to the receptor. The complexes formed are stable and exhibit a similar degree of compactness. Our findings predicted the advent of self-feature extracting machine learning algorithms of compounds, and have provided the possibility of better predictive model quality that is not necessarily limited by compound descriptors. The putative FGFR1 inhibitors, with their mechanism of inhibition and specificity, were elucidated using this approachCommunicated by Ramaswamy H. Sarma.

Role of genetic polymorphism of glutathione-S-transferase T1 and microsomal epoxide hydrolase in aflatoxin-associated hepatocellular carcinoma.

Exposure to aflatoxins is a risk factor for hepatocellular carcinoma (HCC). Aflatoxins occur in peanut butter and are metabolized by genetically polymorphic enzymes such as glutathione-S-transferases encoded by glutathione-S-transferase mu 1 gene (GSTM1) and glutathione-S-transferase theta 1 gene (GSTT1) and microsomal epoxide hydrolase encoded by epoxide hydrolase gene (EPHX). The rate at which aflatoxins become activated or detoxified may depend on polymorphisms in the encoding genes. GSTM1 homozygous deletion was indeed found to modify the association between peanut butter consumption and HCC. In this study, we investigate possible roles of GSTT1 and EPHX polymorphisms in this relationship. From a Sudanese case-control study on HCC, we analyzed data of 112 incident cases and 194 controls. All participants were interviewed using a standardized questionnaire inquiring about social and demographic factors, peanut butter consumption, and other known HCC risk factors. Univariate analysis showed that GSTT1 polymorphism was not associated with HCC, whereas EPHX 113HH and 139HH genotypes increased the risk of HCC (Odds ratio, 3.10; 95% Confidence interval, 1.18-8.12). Adjustment for age and region of origin slightly attenuated this association (Odds ratio, 2.56; 95% Confidence interval, 0.83-7.95). Interestingly, unlike GSTM1, both GSTT1 and EPHX polymorphism did not modify the association between peanut butter consumption and HCC. In conclusion, these epidemiological findings do not suggest significant roles of GSTT1 and EPHX in aflatoxin metabolism, although EPHX polymorphism is possibly related to the increased risk of HCC. Further studies are needed to investigate mechanisms by which the EPHX polymorphism potentially modifies cancer risk.

Peanut butter intake, GSTM1 genotype and hepatocellular carcinoma: a case-control study in Sudan.

OBJECTIVE: Hepatocellular carcinoma (HCC) is one of the major cancers in the world. In Sudan the incidence is thought to be high and increasing. This study aims to assess the association between peanut butter intake, as a source of aflatoxins, and the GSTM1 genotype in the etiology of HCC. METHOD: A case control study was conducted among 150 patients and 205 controls from two regions in Sudan. Food habits with special reference to peanut butter consumption, as well as peanut storage systems, have been investigated, as well as confounders such as hepatitis, drinking and smoking habits, and demographic characteristics. GSTM1 genotype was assessed in DNA extracted from blood samples (110 cases, 189 controls). RESULTS: A positive association was observed for highest vs. lowest quartile of peanut butter intake, humid storage system and HCC, with ORs (95% CI) being 3.0 (1.6-5.5) and 1.6 (1.1-2.5) respectively. The positive association with peanut butter intake was essentially limited to subjects with GSTM1 null genotype with OR for highest vs. lowest quartile 16.7 (2.7-105). CONCLUSION: Peanut butter consumption has been identified as a strong risk factor of HCC in a region with endemic aflatoxin contamination in Sudan and was essentially limited to subjects with the GSTM1 null genotype.

Aflatoxin and liver cancer in Sudan.

This study investigated whether aflatoxin contamination of peanut products may contribute to the incidence of hepatocellular carcinoma (HCC) in Sudan. Thirty-seven peanut butter and peanut samples were collected from local markets. Aflatoxin concentrations were significantly higher in West Sudan [87.4 +/- 197.3 (SD) micrograms/kg], a high-risk area, than in Central Sudan (8.5 +/- 6.8 micrograms/kg), a low-risk area. In West Sudan, humid local storage conditions of peanut products were related to high aflatoxin concentrations. In a small case-control study of HCC patients (n = 24) and controls (n = 34), an odds ratio of 7.5 (95% confidence interval = 1.4-40.2) was observed for humid vs. dry local storage conditions. Development of an index of individual HCC exposure was less successful, probably because of year-to-year variability in aflatoxins in food. These preliminary findings justify further research into the role of aflatoxins and hepatitis in HCC incidence in Sudan.

Survey of some cereal grains and legume seeds for aflatoxin contamination in the Sudan.

Aflatoxins were detected in some cereals and leguminous seeds collected from 2 cities in the Sudan (Wad Medani and Khartoum). The levels of the aflatoxins in these seeds were below the reported hazard threshold. Sound intact seeds contained low or no aflatoxins compared to significantly higher levels detectable in damaged and mouldy seeds of the tested crop plants. The optimum temperature for aflatoxin production was variable for different isolates of A. flavus. The optimum is 30 degrees C for the maize isolate and only 20 degrees C for the haricot bean isolate. Large amounts of aflatoxins B1, B2 and G1 were produced by the 2 isolates while aflatoxin G2 was only produced by the haricot bean isolate at optimum temperature. Aflatoxin B1 had significantly affected seed germination and plant development in both maize and haricot bean plants grown from seeds soaked in aflatoxin solutions. The influence was increasing with increasing concentration of the toxin.