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Drug discovery is still behind in the race compared to vaccine discovery in fighting COVID-19. In this study, we have selected 41 quinazoline alkaloids from two natural product databases to create an adequate library and performed detailed computational studies against the main protease ( M pro ) of SARS-CoV-2 using two reference compounds, namely famotidine and X77. The screening of the library was carried out by blending the rigid docking and pharmacokinetic analysis that resulted in nine alkaloids as initial leads against M pro . These initial leads were further subjected to advanced flexible docking and were compared with reference compounds (famotidine and X77) for the analysis of structure-based interactions. For further selection, a second screening was carried out based on binding energies and interaction profiles that yielded three alkaloids, namely CNP0416047, 3-hydroxy anisotine and anisotine as final leads. The stereo-electronic features of lead alkaloids were further investigated through additional E-pharmacophore mapping against crystallized X77 reference compound. Additionally, the reactivity of lead alkaloids at the binding sites of the protein was estimated by measuring the electron distribution on the frontier molecular orbitals and HOMO–LUMO band energies. Finally, the stabilities of complexes between lead alkaloids with the protein were accessed extensively using robust molecular dynamics simulation through RMSD, RMSF, Rg and MM-PBSA calculation. Thus, this study identifies three natural quinazoline alkaloids as potential lead inhibitors of M pro through extensive computational analysis. This study performed a full-scale in silico investigations on natural quinazoline alkaloids against the main protease (MPro) of SARS_CoV_2 by examining forty one natural quinazoline alkaloids and identified three alkaloids (CNP0416047, 3-hydroxy anisotine and anisotine) as final lead compounds. The screening and structure-based analysis of these ligands were carried out by blending different computational techniques such as rigid docking, pharmacokinetics, flexible docking, E-pharmacophore mapping, DFT studies and MD simulations. Mostly, this study added values to quinazoline alkaloids which are fascinating natural pharmacophores and opened the possibilities of in vitro studies of these hit alkaloids in future. [ABSTRACT FROM AUTHOR]

We have studied the intermolecular complex formation between trifluoromethoxybenzene and methanol (CD3OD) in superfluid helium droplets by infrared spectroscopy in the spectral range of 2630–2730 cm−1, covering the O–D stretches of methanol-d4 (CD3OD). The cluster size associated with the observed bands is deduced from the variation of infrared intensity of a particular band with the partial pressures of trifluoromethoxybenzene and methanol. Quantum chemical calculations are performed at the MP2/6-311++G(d,p) level of theory to complement the experimental results. As a result, we have identified six different conformers of the trifluoromethoxybenzene⋯methanol intermolecular complex: three bound via O–H⋯O hydrogen bonds and the other three via O–H⋯π hydrogen bonds. Furthermore, to access the effect of fluorination on the methyl unit of anisole molecules, we compare the IR spectrum of trifluoromethoxybenzene (C6H5OCF3)⋯methanol with our earlier reported spectrum of anisole (C6H5OCH3)⋯methanol. [ABSTRACT FROM AUTHOR]

The mass-selective infrared (IR) spectra of oxazole-(D2O)n≤2 complexes embedded in helium droplets are recorded in the spectral range of 2565–2800 cm−1. The experimental IR spectra are assigned by comparing with quantum chemical calculations at the MP2/6-311++G(d,p) level of theory. Here, we show that in the case of the 1:1 oxazole-D2O dimer, the water molecule binds to the N atom of the heterocyclic ring via a N⋯DO hydrogen bond (H-bond). However, in the oxazole-(D2O)2 trimer, the water dimer forms N⋯DO and CH⋯O H-bonds with the N atom and adjacent CH group, respectively, leading to the formation of a seven-membered ring. We compare these results with those of our recently reported isoxazole-(water)n≤2 complexes to demonstrate differences in the hydration motif of these two structural isomers. [ABSTRACT FROM AUTHOR]

Hydration of aromatic molecules is a fundamental chemical process. Herein, microhydration framework of the prototypical neutral polycyclic aromatic hydrocarbon (PAH), naphthalene (naphthalene–(water)n≤3), is investigated by infrared spectroscopy inside helium nanodroplets. The measured data are analyzed by quantum chemical calculations at the MP2/6-311++G(d,p) level. This combined experimental and theoretical approach demonstrates that water binds to the naphthalene ring via π hydrogen bond (H-bond) for n = 1 case. Further addition of the solvent molecules occurs via the formation of a H-bonded water network facilitated by the nonadditive cooperative force. No isomers are observed in which the solvent molecules separately bind to the aromatic ring. For n = 3 case, we observe the formation of a cyclic H-bonded water moiety. Comparison with corresponding cationic and anionic naphthalene±–(water)n clusters demonstrates the charge-induced modification of the hydration motif. Our results are further compared with the prototypical benzene–(water)n complexes to comprehend the effect of an additional phenyl ring on the solvation network. [ABSTRACT FROM AUTHOR]

Abstract Background Targeted interventions (TIs) have been a major strategy for HIV prevention in India. We evaluated the impact of TIs on HIV prevalence in high HIV prevalence southern states (Tamil Nadu, Karnataka, Andhra Pradesh and Maharashtra). Methods A quasi-experimental approach was used to retrospectively compare changes in HIV prevalence according to the intensity of targeted intervention implementation. Condom gap (number of condoms required minus condoms supplied by TIs) was used as an indicator of TI intensity. Annual average number of commercial sex acts per female sex worker (FSW) reported in Behavioral Surveillance Survey was multiplied by the estimated number of FSWs in each district to calculate annual requirement of condoms in the district. Data of condoms supplied by TIs from 1995 to 2008 was obtained from program records. Districts in each state were ranked into quartiles based on the TI intensity. Primary data of HIV Sentinel Surveillance was analyzed to calculate HIV prevalence reductions in each successive year taking 2001 as reference year according to the quartiles of TI intensity districts using generalized linear model with logit link and binomial distribution after adjusting for age, education, and place of residence (urban or rural). Results In the high HIV prevalence southern states, the number of TI projects for FSWs increased from 5 to 310 between 1995 and 2008. In high TI intensity quartile districts (n = 30), 186 condoms per FSW/year were distributed through TIs as compared to 45 condoms/FSW/year in the low TI intensity districts (n = 29). Behavioral surveillance indicated significant rise in condom use from 2001 to 2009. Among FSWs consistent condom use with last paying clients increased from 58.6% to 83.7% (p < 0.001), and among men of reproductive age, the condom use during sex with non-regular partner increased from 51.7% to 68.6% (p < 0.001). A significant decline in HIV and syphilis prevalence has occurred in high prevalence southern states among FSWs and young antenatal women. Among young (15-24 years) antenatal clinic attendees significant decline was observed in HIV prevalence from 2001 to 2008 (OR = 0.42, 95% CI 0.28-0.62) in high TI intensity districts whereas in low TI intensity districts the change was not significant (OR = 1.01, 95% CI 0.67-1.5). Conclusion Targeted interventions are associated with HIV prevalence decline.

In this study 1155 injection drug users (IDUs) receiving targeted intervention in five cities of Punjab were surveyed; three cities (Amritsar, Taran-Taran, Batala) were in districts sharing an international border with Pakistan and the other two were Jalandhar and Ludhiana. Information on socio-demography, substance use and sexual practices were collected; blood samples were tested for biologic markers. HIV and HCV antibody (HCVAb) prevalences in injection drug users were 29 and 49%, respectively. Of the HCVAb-seroreactive IDUs, 33% had HIV as well. HIV prevalence in young IDUs (≤19 years), estimated as surrogate for HIV incidence, was high at 12% and HCVAb in this subgroup was 27%. Herpes simplex virus 2 antibody (IgG) was detected in 10% of IDUs; 2% had syphilis. Alcohol use prevalence was high and frequency of use concerning. In multivariate analyses, ‘city of residence closer to international border’ and ‘>1 year duration of injecting drugs were associated with HIV and HCVAb. Furthermore, ‘irregular supply of syringes and needles’ was associated with HCVAb seroreactive status of IDUs (adjusted odds ratio 1.7; 95% CI 1.3–2.3; P < 0.001), and ‘any genital disease symptom within the last year’ (adjusted odds ratio 2; 95% CI 1.4–2.9; P < 0.001) was associated with HIV infection. Alcohol and sexual risk reduction, strengthening of needle–syringe exchange, reducing injecting duration and clinical management of HIV, HCV and HIV/HCV co-infection appear as four core programme needs. [ABSTRACT FROM PUBLISHER]