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IIT Jodhpur

A convergent, robust one-pot three-component approach for the synthesis of dihydrofuro[3,2-c]coumarins (DHFCs) was developed via the reaction of aryl/hetryl aldehydes, substituted phenacyl bromides and 4-hydroxycoumarin using N,N-diisopropyl ethyl ammonium acetate (DIPEAc) as the promoting medium. By virtue of its operational simplicity, efficiency, and wide substrate scope, the herein documented methodology constitutes a very attractive protocol addressing access to diversely substituted fused coumarin derivatives in a cost- and time-effective manner. Moreover, in silico pharmacophore modelling divulges the selective binding of the synthesized DHFC derivatives at the highly conserved active site catalytic cleft of Trichomonas vaginalis purine nucleoside phosphorylase (TvPNP), the indispensable enzyme of the protozoan purine salvage pathway and the potent anti-trichomoniasis drug target. The strong ligand binding is corroborated by excellent free energy of binding (ΔGbinding) profiles and further confirmed by all-atomistic molecular dynamics simulation analysis and deep learning based binding affinity (pKd) predictions. The docked conformations of DHFC derivatives at the active site catalytic cleft of TvPNP are structurally reminiscent of previously reported co-crystallized conformation of FormycinA (PDB ID: <a href="http://xlink.rsc.org/?pdb=1Z36">1Z36</a>), albeit the DHFC derivatives demonstrated stronger binding propensities. Detailed quantitative structure–function analysis, presented herein, may elucidate the potential role of the synthesized DHFC derivatives as future anti-trichomoniasis therapeutic leads.

World University root node

Department of Chemistry

Department of Bioscience & Bioengineering

New Journal of Chemistry

Convenient multicomponent synthesis of furo[3,2-c]coumarins in the promoting medium DIPEAc and assessment of their therapeutic potential through in silico pharmacophore based target screening

The structure of the TriABC inner membrane component of the triclosan/SDS-specific efflux pump from Pseudomonas aeruginosa was determined by cryoelectron microscopy to 4.5 Å resolution. The complete structure of the inner membrane transporter TriC of the resistance-nodulation-division (RND) superfamily was solved, including a partial structure of the fused periplasmic membrane fusion subunits, TriA and TriB. The substrate-free conformation of TriABC represents an intermediate step in efflux complex assembly before the engagement of the outer membrane channel. Structural analysis identified a tunnel network whose constriction impedes substrate efflux, indicating inhibition of TriABC in the unengaged state. Blind docking studies revealed binding to TriC at the same loci by substrates and bulkier non-substrates. Together with functional analyses, we propose that selective substrate translocation involves conformational gating at the tunnel narrowing that, together with conformational ordering of TriA and TriB, creates an engaged state capable of mediating substrate efflux. TriABC is a triclosan/SDS-specific efflux pump from Pseudomonas aeruginosa linked to biocide resistance. Substrate efflux depends on a tunnel in TriC subunits, supported by functional and docking data. Tunnel narrowing by an internal gating loop situated after Val 698 inhibits efflux. Subunits TriA and TriB show disorder in the absence of substrate. © 2020 Elsevier Ltd

Structure

A “Drug Sweeping” State of the TriABC Triclosan Efflux Pump from Pseudomonas aeruginosa

The HIV-1 envelope glycoprotein (Env) (gp120-gp41) 3 is the target for neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC). HIV-1 Env is flexible, sampling different conformational states. Before engaging CD4, Env adopts a closed conformation (State 1) that is largely antibody resistant. CD4 binding induces an intermediate state (State 2), followed by an open conformation (State 3) that is susceptible to engagement by antibodies that recognize otherwise occluded epitopes. We investigate conformational changes in Env that induce ADCC in the presence of a small-molecule CD4-mimetic compound (CD4mc). We uncover an asymmetric Env conformation (State 2A) recognized by antibodies targeting the conserved gp120 inner domain and mediating ADCC. Sera from HIV+ individuals contain these antibodies, which can stabilize Env State 2A in combination with CD4mc. Additionally, triggering State 2A on HIV-infected primary CD4 + T cells exposes epitopes that induce ADCC. Strategies that induce this Env conformation may represent approaches to fight HIV-1 infection. HIV-1 envelope glycoproteins (Env) are very flexible and exist in at least three different conformational states. Alsahafi et al. characterize a fourth Env state that is efficiently recognized by antibodies capable of mediating potent antibody-dependent cellular toxicity. © 2019 Elsevier Inc.

Fulltext

Cell Host and Microbe

An Asymmetric Opening of HIV-1 Envelope Mediates Antibody-Dependent Cellular Cytotoxicity

Nucleosome assembly proteins (Naps) influence chromatin dynamics by directly binding to histones. Here we provide a comprehensive structural and biochemical analysis of a Nap protein from Caenorhabditis elegans (CeNap1). CeNap1 naturally lacks the acidic N-terminal tail and has a short C-terminal tail compared to many other Nap proteins. Comparison of CeNap1 with full length and tail-less constructs of Saccharomyces cerevisiae Nap1 uncovers the role of these tails in self-association, histone binding, and Nap competition with DNA for H2A-H2B. We find that the presence of tails influences the stoichiometry of H2A-H2B binding and is required to complete the interactions between H2A-H2B and DNA. The absolute stoichiometry of the Nap protein and H2A-H2B complex is 2:1 or 2:2, with only a very small population of higher-order oligomers occurring at 150 mM NaCl. We also show that H3-H4 binds differently than H2A-H2B and that an (H3-H4) 2 tetramer can simultaneously bind two Nap 2 protein homodimers. © 2018 American Chemical Society.