Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have shown a lot of promise, yet their use has been limited in treating HIV-1 infection. In order to improve low treatment success rates, owing to the resistance developed, cross-resistance derived from mutational changes and fatal side-effects, modified and novel NNRTIs with better pharmacokinetic efficacies are required. In an effort to design novel NNRTIs, we report 3D structure-activity relationship (SAR) quantifying pharmacophoric descriptors (S ALL , HD ALL , HA ALL , R ALL and POS ALL ), generated from the similarity based alignment of molecules with respect to the group centre overlap from each individual template point. The 3D pharmacophore based mapping of the compounds and subsequent comparison with respect to the bridging groups S/SO/SO 2 and the substituents on rings 'A' and 'B' yielded good results. Also, statistical modeling of the 3D structural parameters was performed on the aforementioned series, with noteworthy results (ANN: r 2 = 0.914, MLR: r 2 = 0.902). The findings were well-reciprocated while cross-validating using a test-set (ANN: r 2 = 0.855, MLR: r 2 = 0.805). These findings and analyses warrant further development of these series of compounds to enhance their medicinal application for the treatment of AIDS in both NNRTI-experienced and -naı ¨ve patients.

Six novel non-nucleoside reverse transcriptase inhibitors exhibiting high efficacy are designed using in silico mathematical modelling techniques and the results are validated using a docking technique. An in silico assessment of interaction potential and structural requirements of 5-alkyl-2-alkylamino-6-(2,6difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-one (DABO) analogues in the non-nucleoside inhibitor binding pocket is also performed. Efficient use of 3D-pharamacophoric (S ALL , HD ALL , HA ALL and R ALL ) and 3D-averaged alignment (C log P and dipole moment) descriptors is made in this study. The chemometric analyses, using support vector machine, back propagation neural network and multiple linear regression, are performed. The relative potentials of these chemometric methods is also assessed and the results,indicates that SVM describes the relationship between the descriptors and inhibitory activity in a better manner. The results also suggest that there is a non-linear relationship between the descriptors and inhibitory activity. The study further suggests that isopropyl/propenyl groups as R and R 0 , oxobutyl group as X and di or tri-substitution as R 00 are the best suited substituents for exhibiting better inhibitory activity.View Article Online a pEC 50 ¼ Àlog EC 50 (where EC 50 is the effective concentration of a compound required to activate 50% protection of MT-4 cell against the cytopathic effect of HIV-1). The data points a represent the test set and b as Outliers.This journal is

In silico studies were performed using 5-fluorouracil (5-FU) to explore the efficacy of template docking and facilitate designing of drug nanocarrier systems. The binding of human uridine phosphorylase (huPP1) with 5-FU was found to show the following interactions: (1) hydrogen bonds were alleviated by a network of GLN217 and ARG219, (2) hydrophobic interactions were shown by PHE213, THR141, LEU272, and ILE281 (3) positive electrostatic interactions were shown by PHE213, THR141, LEU272, SER142, GLU248, and GLY143. As an experimental supplementation and validation to the adopted computational approach, 5- FU-loaded soya protein-coated iron oxide (SPCIO) core–shell nanoparticles were prepared following microemulsion and co-precipitation techniques and subsequently characterized by FTIR, particle size and zeta potential studies, TEM, XRD, and DSC techniques. Whereas the FTIR spectra confirm the presence of the soya protein and drug 5-FU in the nanoparticles, the zeta potential was found to be suppressed due to the loading of 5-FU. The XRD study confirmed the crystalline nature of the drug-loaded nanoparticles. TEM analysis suggested that the nanoparticles have sizes up to 200 nm and the morphology and size remain almost the same even after loading of the drug 5-FU onto nanoparticles. The soya protein-coated iron oxide nanoparticles demonstrated zero cytotoxicity against fibroblast cells. The controlled release of 5-FU was studied in vitro, and the effects of pH, chemical composition of nanoparticles, extent of drug loading, and simulated biofluids on the controlled release of 5-FU were studied. The swelling of nanoparticles and release of 5-FU were found to increase with increasing strength of the externally applied magnetic field.

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The paper presents the incorporation of in silico missenses and studies the effect of missenses to understand its effect on the Ligand-Protein interactions, of COVID-19 protein. In silico protein-ligand interaction, studies are being used to understand and investigate the drug-likeness of various molecules. 19 novel COVID-19 proteins are designed by inducing in silico missenses by mutating N691 amino acid residue in 7bv2 protein, the only residue forming H-bond with the ligand molecule in the parent protein. The work illustrates the effects of in silico-induced mutation on various interactions such as H-Bond, VDW, π-alkyl interactions, and changes in the number and type of surrounding amino acid residues. The results have suggested a common pattern of behaviour on mutation with T, V, W, and Y. Further, it is observed that the number and type of amino acid residues increase on mutation, suggesting the effect of mutation on the ligand-protein binding.