Machine learning-based predictive models for identifying high active compounds against HIV-1 integrase.

HIV-integrase is an important drug target because it catalyzes chromosomal integration of proviral DNA towards establishing latent infection. Computer-aided drug design has immensely contributed to identifying and developing novel antiviral drugs. We have developed various machine learning-based predictive models for identifying high activity compounds against HIV-integrase. Multiclass models were built using support vector machine with reasonable accuracy on the test and evaluation sets. The developed models were evaluated by rigorous validation approaches and the best features were selected by Boruta method. As compared to the model developed from all descriptors set, a slight improvement was observed among the selected descriptors. Validated models were further used for virtual screening of potential compounds from ChemBridge library. Of the six high active compounds predicted from selected models, compounds 9103124, 6642917 and 9082952 showed the most reasonable binding-affinity and stable-interaction with HIV-integrase active-site residues Asp64, Glu152 and Asn155. This was in agreement with previous reports on the essentiality of these residues against a wide range of inhibitors. We therefore highlight the rigorosity of validated classification models for accurate prediction and ranking of high active lead drugs against HIV-integrase.

Antiproliferative activity of novel thiophene and thienopyrimidine derivatives.

A novel series of newly synthesized thiophene derivatives, ethyl-4,5-dimethyl-2-(3-(3,4,5-trimethoxyphenyl)thioureido)thiophene-3-carboxylate 3, ethyl-2-[(2-(dimethylamino)ethoxy)mercapto)methyleneamino)]-4,5-dimethyl-thiophene-3-carboxylate 9, thienopyrimidines 4, 7, 10-20, triazolothienopyrimidines 5, 6 were prepared and tested for their antiproliferative activity. The structures of the synthesized compounds were confirmed on the basis of elemental analysis, IR, (1)H-NMR, (13)C-NMR and mass spectral data. The results showed that the synthesized compounds were more active on breast cancer than on colon cancer cell lines and the most potent compounds in this study are compounds 3 and 13 which exerted remarkable activity against MDA-MB-231 (breast cancer) and HT-29 (colon cancer) cell lines with IC50 values (40.68, 49.22 µM) for compound 3 and (34.04, 45.62 µM) for compound 13. Also, compounds 4-6, 9 showed a moderate activity against breast cancer cell line, while compounds 15, 19 and 20 showed no activity.

Synthesis, anticancer activity and radiosensitizing evaluation of some new 2-pyridone derivatives.

Based on the reported anticancer activity of 2-pyridone, a new series of 6-amino-5-cyano-1-(3-ethylphenyl)-2-oxo-4-substituted-1,2-dihydropyridine-3-carbo-nitriles 4a-p were synthesized and tested for in-vitro anticancer activity against Ehrlich Ascites Carcinoma (EAC) cell line and liver human tumor cell line (HEPG2). Radiosensitizing activity was also evaluated. The starting material 2-cyano-N-(3-ethylphenyl)-acetamide 3 was obtained via reaction of 3-ethyl aniline 1 with ethyl cyanoacetate under condition of fusion. Upon treatment of compound 3 with aromatic aldehyde and malononitrile in the presence of catalytic amount of piperidine yielded the corresponding 1,2-dihydropyridine derivative 4a-p. Also chromenes 5 and 6 were obtained in good yield via reaction of compound 3 with salicyladehyde under different condition. The chromene derivatives 5 and 6 were further reacted with malononitrile in NH4OAc, afford the corresponding chromenopyridones 7 and 8. The structures of the synthesized compounds 3-8 were confirmed by analytical and spectral data. Compounds 4d, 4e, 5 and 6 showed higher anticancer activity against EAC cell line with IC50 values (75.32, 20.77, 73.1 and 67.05 µM) compared to doxorubicin as positive control with IC50 value (68.13 µM), moreover, these compounds showed potent activity on HEPG2 cell line with IC50 values (26.5, 19.2, 39.3, 44.9 µM), respectively, compared to doxorubicin (CAS 29042-30-6) (38.46 µM) and their activity increased synergistically when combined with γ-radiation.

Determination of the natural radioactivity levels in north west of Dukhan, Qatar using high-resolution gamma-ray spectrometry.

This study is aimed at the determination of the activity concentrations of naturally occuring and technologically enhanced levels of radiation in 34 representative soil samples that have been collected from an inshore oil field area which was found to have, in a previous study, the highest observed value of 226Ra concentration among 129 soil samples. The activity concentrations of 238U and 226Ra have been inferred from gamma-ray transitions associated with their decay progenies and measured using a hyper-pure germanium detector. Details of the sample preparation and the gamma-ray spectroscopic analysis techniques are presented, together with the values of the activity concentrations associated with the naturally occuring radionuclide chains for all the samples collected from NW Dukhan. Discrete-line, gamma-ray energy transitions from spectral lines ranging in energy from ∼100 keV up to 2.6 MeV have been associated with characteristic decays of the various decay products within the 235.8U and 232Th radioactive decay chains. These data have been analyzed, under the assumption of secular equilibrium for the U and Th decay chains. Details of the sample preparation and the gamma-ray spectroscopic analysis techniques are presented. The weighted mean value of the activity concentrations of 226Ra in one of the samples was found to be around a factor of 2 higher than the values obtained in the previous study and approximately a factor of 10 higher than the accepted worldwide average value of 35 Bq/kg. The weighted mean values of the activity concentrations of 232Th and 40K were also deduced and found to be within the worldwide average values of 30 and 400 Bq/kg, respectively. Our previous study reported a value of 201.9±1.5Stat.±13Syst.Bq/kg for 226Ra in one sample and further investigation in the current work determined a measured value for 226Ra of 342.00±1.9Stat.±25Syst.Bq/kg in a sample taken from the same locality. This is significantly higher than all the other investigated soil samples in the current and previous works. Notably, the Th levels in the same sample are within the worldwide average expectations, implying that the increased 226Ra concentration arises from TENORM processes.

Ocular manifestations of branchio-oculo-facial syndrome: report of a novel mutation and review of the literature.

PURPOSE: To report unusual ocular manifestations of branchio-oculo-facial syndrome (BOFS) caused by a novel mutation in activating enhancer binding protein 2 alpha (TFAP2A). METHODS: Full ophthalmological evaluation and direct sequencing of TFAP2A. RESULTS: A 10-year-old girl with unusual ocular manifestations of BOFS such as elliptical shaped microcornea and a novel de novo TFAP2A mutation was identified. CONCLUSIONS: This report expands the ocular phenotypic spectrum of BOFS and adds to the small number of reported TFAP2A mutations.

Zellweger syndrome caused by PEX13 deficiency: report of two novel mutations.

Peroxisomal biogenesis disorders represent a group of genetically heterogeneous conditions that have in common failure of proper peroxisomal assembly. Clinically, they are characterized by a spectrum of dysmorphia, neurological, liver, and other organ involvement. To date, mutations in 13 PEX genes encoding peroxins have been identified in patients with peroxisomal biogenesis disorders. Mutations in PEX13, which encodes peroxisomal membrane protein PEX13, are among the least common causes of peroxisomal biogenesis disorders with only three mutations reported so far. Here, we report on two infants whose clinical and biochemical profile was consistent with classical Zellweger syndrome and whose complementation analysis assigned them both to group H of peroxisomal biogenesis disorders. We show that they harbor two novel mutations in PEX13. One patient had a genomic rearrangement resulting in a 147 kb deletion that spans the whole of PEX13, while the other had an out-of-frame deletion of 14 bp. This represents the first report of a PEX13 deletion and suggests that further work is needed to examine the frequency of PEX13 mutations among Arab patients with peroxisomal biogenesis disorders.