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.

Enhanced immunogenicity of recombinant hepatitis B vaccine in exposed family contacts of chronic liver disease patients.

Close family contacts of hepatitis B virus (HBV)-related chronic liver disease patients have a high risk of exposure to HBV. Variable responses to vaccination have been reported in family contacts, especially in previously exposed contacts (IgG antiHBc-positive). Seventy-nine healthy family contacts, who were HBsAg-negative with normal alanine amino-transferase level and no evidence of liver disease, were vaccinated using a recombinant HBV vaccine, irrespective of past exposure status. A significantly higher number of previously exposed subjects (n = 25; Group I) developed early seroprotective anti-HBs titers with 2 initial doses of vaccine compared to the unexposed contacts (Group II; n = 54) (64% vs. 33%, respectively; P < 0.05). However, the responses were comparable on completion of the schedule (96% vs. 94%, respectively). HBV DNA was detected in 11 of 25 (44%) exposed and none of the unexposed contacts at baseline. Post-vaccination, 3 of 11 (27%) subjects became HBV DNA-negative and remained negative for the next 12 months. These results suggest that exposed family contacts achieve efficient seroprotection after HBV vaccination, irrespective of the IgG anti-HBc status. The response to vaccination resembles an anamnestic reaction and possibly demonstrates a therapeutic effect.

Base-pair alterations in the epsilon-lower stem due to a novel double substitution in the precore gene of HBV-e negative variant were recovered by secondary mutations.

The HBe negative phenotype, a natural precore mutant (G1896A/G1897A) of HBV with aborted HBeAg expression is known to cause chronic hepatitis. The destabilized C : G base-pairing in the lower stem of epsilon-hairpin due to G1896A substitution is reportedly compensated by a second C1858T mutation and suggested to play an important role in enhanced selection of the HBe negative variant. We undertook to investigate presence of such compensatory mutations at other positions by analyzing epsilon-sequences (nts. 1847-1907) as well as to look for their effect(s), if any, on the consensus sequence of the overlapping core-initiator of HBe negative HBV variants in CLD patients. Three of the 5 HBe negative patients had classical G1896A mutation having a second compensatory mutation at nt. 1858. One patient showed an additional G1897A substitution, presenting as a novel precore stop codon mutation (UGG-->UAA), followed by a compensatory mutation at position 1857. In the third patient, a G1899A substitution was seen which compensated the impaired U at position 1855. Other substitution and deletion mutations were also observed in the remaining epsilon-hairpin, which however, did not produce any compensatory mutation. Further, all the precore variants showed a conserved G at position 1904, important for the optimal context of their core-initiator which however, remained impaired with A (nt. 1850). Our results suggest that the nts. 1851-1859 and nts. 1895-1904 in the lower stem, and restoration of authentic base-pairings therein, maintain the structural integrity and stability of the epsilon-hairpin. This may have a role in the enhanced selection of the HBe negative variants and persistence of HBV infection in chronic liver disease patients.