43 research outputs found

    Molecular Modeling Study on the Allosteric Inhibition Mechanism of HIV-1 Integrase by LEDGF/p75 Binding Site Inhibitors

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    <div><p>HIV-1 integrase (IN) is essential for the integration of viral DNA into the host genome and an attractive therapeutic target for developing antiretroviral inhibitors. LEDGINs are a class of allosteric inhibitors targeting LEDGF/p75 binding site of HIV-1 IN. Yet, the detailed binding mode and allosteric inhibition mechanism of LEDGINs to HIV-1 IN is only partially understood, which hinders the structure-based design of more potent anti-HIV agents. A molecular modeling study combining molecular docking, molecular dynamics simulation, and binding free energy calculation were performed to investigate the interaction details of HIV-1 IN catalytic core domain (CCD) with two recently discovered LEDGINs BI-1001 and CX14442, as well as the LEDGF/p75 protein. Simulation results demonstrated the hydrophobic domain of BI-1001 and CX14442 engages one subunit of HIV-1 IN CCD dimer through hydrophobic interactions, and the hydrophilic group forms hydrogen bonds with HIV-1 IN CCD residues from other subunit. CX14442 has a larger <i>tert</i>-butyl group than the methyl of BI-1001, and forms better interactions with the highly hydrophobic binding pocket of HIV-1 IN CCD dimer interface, which can explain the stronger affinity of CX14442 than BI-1001. Analysis of the binding mode of LEDGF/p75 with HIV-1 IN CCD reveals that the LEDGF/p75 integrase binding domain residues Ile365, Asp366, Phe406 and Val408 have significant contributions to the binding of the LEDGF/p75 to HIV1-IN. Remarkably, we found that binding of BI-1001 and CX14442 to HIV-1 IN CCD induced the structural rearrangements of the 140 s loop and oration displacements of the side chains of the three conserved catalytic residues Asp64, Asp116, and Glu152 located at the active site. These results we obtained will be valuable not only for understanding the allosteric inhibition mechanism of LEDGINs but also for the rational design of allosteric inhibitors of HIV-1 IN targeting LEDGF/p75 binding site.</p></div

    The LEDGF/p75 protein residues contribution to the total binding free energy of the LEDGF/p75 bound HIV-1 IN CCD complex.

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    <p>The LEDGF/p75 protein residues contribution to the total binding free energy of the LEDGF/p75 bound HIV-1 IN CCD complex.</p

    Per-residue interaction spectrum of the residues of HIV-1 IN CCD with (A) BI-1001, (B) CX14442, and (C) LEDGF/p75 in complex with the HIV-1 IN CCD dimer from MM/GBSA free energy decomposition analysis.

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    <p>Per-residue interaction spectrum of the residues of HIV-1 IN CCD with (A) BI-1001, (B) CX14442, and (C) LEDGF/p75 in complex with the HIV-1 IN CCD dimer from MM/GBSA free energy decomposition analysis.</p

    Structural model of LEDGF/p75 in complex with HIV-1 IN CCD dimer.

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    <p>The averaged structure extracted from the MD trajectory was used. The protein is shown in cartoon representation with two monomers in yellow and cyan. The side chains of the LEDGF/p75 amino acids are shown as gray sticks. Hydrogen bond interactions are denoted by dotted green lines.</p

    Scheme of the active site DDE motif (Asp64, Asp116, and Glu152) models for (A) LEDGF/p75, (B) BI-1001 and (C) CX14442 bound HIV-1 IN complexes.

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    <p>The measured distances between the centroid of the side chains of the three conserved catalytic residues were labeled in each model.</p

    The monitored RMSD of the backbone atoms of protein (black), backbone atoms of binding pocket residues around 5 Å of ligand (blue), and the heavy atoms in the ligand (red) for: (A) BI-1001 and (B) CX14442 bound HIV-1 IN complexes with respect to the initial structures as a function of time.

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    <p>(C) The monitored RMSD of the backbone atoms of HIV-1 IN and LEDGF/p75 (black), backbone atoms of HIV-1 IN (blue), and backbone atoms of LEDGF/p75 (red) for LEDGF/p75 bound HIV-1 IN complex with respect to the initial structures as a function of time.</p

    The aligned representative conformations of BI-1001, CX14442, and LEDGF/p75 bound HIV-1 IN CCD dimer models.

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    <p>The averaged structures extracted from the MD trajectories were used. The BI-1001, CX14442, and LEDGF/p75 bound form are shown in yellow, cyan and gray, respectively. HIV-1 IN active site residues (Asp64, Asp116, and Glu152) are shown in stick. The LEDGINs and LEDGF/p75 are represented in stick and carton, respectively.</p

    Electrostatic potential surface of the allosteric binding pocket of HIV-1 IN CCD dimer in interaction with (A) BI-1001, (B) CX14442, and (C) LEDGF/p75.

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    <p>The positive charges are displayed in blue, negative charges are displayed in red, and neutral residues are displayed in white. Color intensity is proportional to the charge value. The BI-1001, CX14442 and side chain of the LEDGF/p75 key residues, whose carbon atoms are shown as green spheres and labeled as red. The residue Trp131 from monomer A of HIV-1 CCD dimer is also labeled (black).</p

    The generated pharmacophore for HIV-1 IN LEDGINs based on the receptor-ligand interactions.

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    <p>The model consists of hydrophobic and hydrophilic features on LEDGINs as well as the key residue in HIV-1 IN allosteric site. The hydrophobic and hydrophilic domains are shown in green and red, respectively. The residues that participated in the interaction between LEDGINs and HIV-1 IN CCD are labeled in cyan and orange, while the potential residues used for further extension LEDGINs design are labeled in black and gray.</p

    Structure of LEDGINs and HIV-1 IN CCD dimer.

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    <p>(A) Chemical structures of BI-1001 and CX14442. (B) Crystal structure of BI-1001 bound to the HIV-1 IN CCD dimer interface (PDB ID code 4DMN). The monomers are distinguished in yellow and cyan, and the BI-1001 is shown in gray stick model. The constructed missing loop (residues 141 to 151) is colored gray. The allosteric site at the HIV-1 IN CCD dimer interface is represented by surface. HIV-1 IN active site residues (Asp64, Asp116, and Glu152) are shown in cyan stick.</p
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