Pharmacophore modelling-based drug repurposing approaches for monkeypox therapeutics.

Monkeypox is a zoonotic viral disease that mainly affects tropical rainforest regions of central and west Africa, with sporadic exportations to other places. Since there is no cure, treating monkeypox with an antiviral drug developed for smallpox is currently acceptable. Our study mainly focused on finding new therapeutics to target monkeypox from existing compounds or medications. It is a successful method for discovering or developing medicinal compounds with novel pharmacological or therapeutic applications. In this study, homology modelling developed the Monkeypox VarTMPK (IMNR) structure. Ligand-based pharmacophore was generated using the best docking pose of standard ticovirimat. Further, molecular docking analysis showed compounds, tetrahydroxycurcumin, procyanidin, rutin, vicenin-2, kaempferol 3-(6''-malonylglucoside) were the top five binding energy compounds against VarTMPK (1MNR). Furthermore, we carried out MD simulations for 100 ns for the six compounds, including reference based on the binding energies and interactions. MD studies revealed that as ticovirimat interacted with residues Lys17, Ser18, and Arg45, all the above five compounds interacted with the same amino acids at the active site during docking and simulation studies. Among all the compounds, ZINC4649679 (Tetrahydroxycurcumin) was shown to have the highest binding energy -9.7 kcal/mol and also observed stable protein-ligand complex during MD studies. ADMET profile estimation showed that the docked phytochemicals were safe. However, further biological assessment through a wet lab is essential to measure the efficacy and safety of the compounds.Communicated by Ramaswamy H. Sarma.

Targeting a conserved pocket (n-octyl-ß-D-glucoside) on the dengue virus envelope protein by small bioactive molecule inhibitors.

Dengue virus enters the cell by receptor-mediated endocytosis followed by a viral envelope (DENVE) protein-mediated membrane fusion. A small detergent molecule n-octyl-ß-D-glucoside (ßOG) occupies the hydrophobic pocket which is located in the hinge region plays a major role in the rearrangement. It has been reported that mutations occurred in this binding pocket lead to the alterations of pH threshold for fusion. In addition to this event, the protonation of histidine residues present in the hydrophobic pocket would also impart the conformational change of the E protein evidence this pocket as a promising target. The present study identified novel cinnamic acid analogs as significant blockers of the hydrophobic pocket through molecular modeling studies against DENVE. A library of seventy-two analogs of cinnamic acid was undertaken for the discovery process of DENV inhibitors. A Molecular docking study was used to analyze the binding mechanism between these compounds and DENV followed by ADMET prediction. Binding energies were predicted by the MMGBSA study. The Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. The compounds CA and SCA derivatives have been tested against HSV-1 & 2 viruses. From the computational results, the compounds CA1, CA2, SCA 60, SCA 57, SCA 37, SCA 58, and SCA 14 exhibited favorable interaction energy. The compounds have in-vitro antiviral activity; the results clearly indicate that the compounds showed the activity against both the viruses (HSV-1 & HSV-2). Our study provides valuable information on the discovery of small molecules DENVE inhibitors.Communicated by Ramaswamy H. Sarma.