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AbstractThe molecular chaperone heat shock protein 90 (Hsp90) has emerged as one of the most exciting targets for anticancer drug development and Hsp90 inhibitors are potentially useful chemotherapeutic agents in cancer. Within the current study, Hsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 structure query to find similar compounds (≥ 78%). Obtained small molecules (1-29) with defined similarity cut-off were docked into ensemble of Hsp90-α NTDs. Docked complexes were ranked on the basis of binding modes and Gibbs free energies as Hsp90 binders (cut-off point; ΔGb≤ −12 kcal/mol). Top-ranked compounds were subjected to energy decomposition analysis per residue of binding pocket via density functional theory (DFT) calculations in B3LYP level of theory. Subsequent MD simulations of the top-ranked complexes were performed for 100 ns to explore the stable binding modes during a reasonable period in explicit water. Results of molecular docking and intermolecular binding analysis indicated that H-bond, hydrophobic and salt bridge interactions were determinant forces in complex formation. Compounds 19and 20were well accommodated in binding pocket of Hsp90 via relatively varied conformations. It was revealed that Asn51 and Phe138 were key residues that interacted stably to 19and 20. Although primary mechanism of action for proposed molecules are unknown and yet to be explored, results of the present study revealed key structural features for future structure-guided optimization toward potent inhibitors of Hsp90-α NTD. HighlightsHsp90 inhibitors that entered different phases of clinical trials were subjected to Zinc15 based structure query to afford potential enzyme inhibitors 19and 20.Quantum chemical calculations confirmed docking results and verified pivotal role of a conserved residues (Asn51, Leu103, Phe138 and Tyr139) in making effective hydrogen bonds.MD simulations of top-ranked docked derivatives revealed the achievement of stable binding modes with less conformational variation of 20than 19in the active site of Hsp90-α NTD.H-bond, hydrophobic contacts and salt bridge interactions were determinant forces in binding interactions of in silicohits.Resorcinol and isoxazole were important structural motifs of in silicohits in binding to the active site of Hsp90-α NTD.Communicated by Ramaswamy H. Sarma

AbstractConsidering lack of validated therapeutic drugs or vaccines against contagious SARS-CoV2, various efforts have been focused on repurposing of existing drugs or identifying new agents. In an attempt to identify new and potential SARS-CoV2 inhibitors targeting specific enzyme of the pathogen, a few induced fit models of SARS-CoV2 main protease (Mpro) including N-aryl amide and aryl sulfonamide based fragments were subjected to a multi-step in silicostrategy. Sub-structure query of co-crystallographic fragments provided numerous ZINC15 driven commercially available compounds that entered molecular docking stage to find binding interactions/modes inside Mpro active site. Docking results were reevaluated through time dependent stability of top-ranked ligand-protease complexes by molecular dynamics (MD) simulations within 50 ns. Relative contribution of interacted residues in binding to the most probable binding pose was estimated through amino acid decomposition analysis in B3LYP level of theory with Def2-TZVPP split basis set. In confirmation of docking results, MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔGb−9.18 kcal/mol) into Mpro active site. H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silicohit. Quantum chemical calculations confirmed MD results and proved the pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772. Drug-like physicochemical properties as well as desirable target binding interactions nominated ZINC_252512772 as a desirable in silicohit for further development toward SARS-CoV2 inhibitors. HighlightsA few N-aryl amide/aryl sulfonamide based fragments were subjected to a multi-step in silicostrategy to afford potential SARS-CoV2 Mpro inhibitors.MD simulations revealed less perceptible torsional distortions (more stable binding mode) in binding of ZINC_252512772 (ΔGb-9.18 kcal/mol) into Mpro active site.H-bond interactions and hydrophobic contacts were determinant forces in binding interactions of in silicohit.Quantum chemical calculations confirmed MD results and proved pivotal role of a conserved residue (Glu166) in making permanent hydrogen bond (98% of MD simulations time) with ZINC_252512772.Communicated by Ramaswamy H. Sarma

AbstractAlzheimer’s disease is a progressive neurodegenerative disorder and patients suffer from memory loss, a decline in language skill and impairment in other cognitive functions. In the cholinergic hypothesis, dysfunction of cholinergic neurons especially in the hippocampus and cerebral cortex contributes to cognitive decline in patients. So agents that enhance acetylcholine concentration could improve cognitive function. AChEIs are among the most studied anti-Alzheimer agents. Galbanic acid as a natural compound with a sesquiterpene coumarin scaffold is a weak inhibitor of AChE. In the present contribution, we discussed the impact of carboxylic group ionization on inhibitory effects. We performed in vitroand in silicostudies on galbanic acid, methyl and ethyl galbanates as AChE inhibitors. The order of inhibitory effect on AChE was obtained as ethyl galbanate ∼ methyl galbanate > galbanic acid. Our study highlights the important role of the physicochemical properties of natural lead compounds in each specific assay.Communicated by Ramaswamy H. Sarma

AbstractMicrotubule is one of the most studied targets in cancer research. Stabilizing and destabilizing of the microtubule by targeting its building block tubulin are common mechanisms of microtubule targeting agents. Cancer associates inversely with Alzheimer’s disease (AD). So the rate of developing AD is significantly slower in patients with cancer and vice versa. Amyloid-β (Aβ) peptide inhibits tubulin polymerization and induces apoptotic death of cancer cells. We studied the interactions of Aβ with tubulin using protein-protein docking and MD simulation. Aβ bond to the vicinity of the vinblastine binding site and interacted with the H6-H7 loop. Interaction of Aβ with H6-H7 loop blocked nucleotide exchange and may be attributed as a possible reason for blocking of tubulin polymerization. We designed new Aβ-based peptidic inhibitors of tubulin using visual inspection and alanine scanning method. P1(FRHYHHFFELV) and P9(HYHHF) bound efficiently to tubulin and also interacted with the H6-H7 loop. Obtained results indicated that proposed peptides could potentially inhibit nucleotide exchange as Aβ.Communicated by Ramaswamy H. Sarma