Computational screening of medicinal plant phytochemicals to discover potent pan-serotype inhibitors against dengue virus.

Emergence of Dengue as one of the deadliest viral diseases prompts the need for development of effective therapeutic agents. Dengue virus (DV) exists in four different serotypes and infection caused by one serotype predisposes its host to another DV serotype heterotypic re-infection. We undertook virtual ligand screening (VLS) to filter compounds against DV that may inhibit inclusively all of its serotypes. Conserved non-structural DV protein targets such as NS1, NS3/NS2B and NS5, which play crucial role in viral replication, infection cycle and host interaction, were selected for screening of vital antiviral drug leads. A dataset of plant based natural antiviral derivatives was developed. Molecular docking was performed to estimate the spatial affinity of target compounds for the active sites of DV's NS1, NS3/NS2B and NS5 proteins. The drug likeliness of the screened compounds was followed by ADMET analysis whereas the binding behaviors were further elucidated through molecular dynamics (MD) simulation experiments. VLS screened three potential compounds including Canthin-6-one 9-O-beta-glucopyranoside, Kushenol W and Kushenol K which exhibited optimal binding with all the three conserved DV proteins. This study brings forth novel scaffolds against DV serotypes to serve as lead molecules for further optimization and drug development against all DV serotypes with equal effect against multiple disease causing DV proteins. We therefore anticipate that the insights given in the current study could be regarded valuable towards exploration and development of a broad-spectrum natural anti-dengue therapy.

A computational structural analysis of functional attributes of hypodermin A and B proteins: A way forward for vaccine development.

Hypodermosis is a parasitic disease of cattle. The pathogenicity of the disease is attributed to Hypodermin proteins (Hypodermin A, Hypodermin B and Hypodermin C). Studies suggest that Hypodermin proteins may be defined as Serine proteases and collagenases. The structure of both proteases Hypodermin A and Hypodermin B were modeled using the Swiss-model server followed by its validation using Procheck, Errat and Verify-3D. Afterwards, both Hypodermin A and Hypodermin B were docked against collagen in order to study its interaction with respective Hypodermin proteins. The structure of both Hypodermin A and Hypodermin B showed more bent towards hydrophobic nature as more beta sheets were present in them. Both structures were also superimposed to check out similarities and differences present between them. Serine, Aspartic acid, Histidine, Glutamic acid and Lysine are found as interacting residues that are involved in hydrogen bonding with collagen. The interactions are found in the active domain region of Hypodermin proteins. The interacting residues were present in the active region of the hypodermin proteins thus validating the docking studies. This study may help in the drug development against hypodermosis with least side effects.

Design, synthesis, characterization and computational docking studies of novel sulfonamide derivatives.

This study reports three novel sulfonamide derivatives 4-Chloro-N-[(4-methylphenyl) sulphonyl]-N-propyl benzamide (1A), N-(2-hydroxyphenyl)-4-methyl benzene sulfonamide (1B) and 4-methyl-N-(2-nitrophenyl) benzene sulfonamide (1C). The compounds were synthesised from starting material 4-methylbenzenesulfonyl chloride and their structure was studied through 1H-NMR and 13C-NMR spectra. Computational docking was performed to estimate their binding energy against bacterial p-amino benzoic acid (PABA) receptor, the dihydropteroate synthase (DHPS). The derivatives were tested in vitro for their antimicrobial activity against Gram+ and Gram- bacteria including E. coli, B. subtilis, B. licheniformis and B. linen. 1A was found active only against B. linen; 1B was effective against E. coli, B. subtilis and B. linen whereas 1C showed activity against E. coli, B. licheniformis and B. linen. 1C showed maximum activity with minimum inhibitory concentration (MIC) of 50, 100 and 150 µg/mL against E. coli, B. licheniformis and B. linen respectively. 1C exhibited maximum affinity to DHPS with binding free energy of -8.1 kcal/mol. It enriched in the top 0.5 % of a library of 7663 compounds, ranked in order of their binding affinity against DHPS. 1C was followed by 1B which showed a moderate to low level MIC of 100, 250 and 150 µg/mL against E. coli, B. subtilis and B. linen respectively, whereas 1A showed a moderate level MIC of 100 µg/mL but only against B. linen. These derivatives may thus serve as potential anti-bacterial alternatives against resistant pathogens.