Fragment-based virtual screening approach and molecular dynamics simulation studies for identification of BACE1 inhibitor leads

<p>Traditional structure-based virtual screening method to identify drug-like small molecules for BACE1 is so far unsuccessful. Location of BACE1, poor Blood Brain Barrier permeability and P-glycoprotein (Pgp) susceptibility of the inhibitors make it even more difficult. Fragment-based drug design method is suitable for efficient optimization of initial hit molecules for target like BACE1. We have developed a fragment-based virtual screening approach to identify/optimize the fragment molecules as a starting point. This method combines the shape, electrostatic, and pharmacophoric features of known fragment molecules, bound to protein conjugate crystal structure, and aims to identify both chemically and energetically feasible small fragment ligands that bind to BACE1 active site. The two top-ranked fragment hits were subjected for a 53 ns MD simulation. Principle component analysis and free energy landscape analysis reveal that the new ligands show the characteristic features of established BACE1 inhibitors. The potent method employed in this study may serve for the development of potential lead molecules for BACE1-directed Alzheimer’s disease therapeutics.</p

Computational profiling of pore properties of outer membrane proteins

Computational profiling of pore properties of outer membrane protein

Modeling the Closed and Open State Conformations of the GABA_A Ion Channel - Plausible Structural Insights for Channel Gating

Recent disclosure of high resolution crystal structures of <i>Gloeobacter violaceus</i> (GLIC) in open state and <i>Erwinia chrysanthemii</i> (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA_A ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β₂ and Arg207β₂) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl^– ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states

Modeling the Closed and Open State Conformations of the GABA_A Ion Channel - Plausible Structural Insights for Channel Gating

Recent disclosure of high resolution crystal structures of <i>Gloeobacter violaceus</i> (GLIC) in open state and <i>Erwinia chrysanthemii</i> (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA_A ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β₂ and Arg207β₂) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl^– ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states

Modeling the Closed and Open State Conformations of the GABA_A Ion Channel - Plausible Structural Insights for Channel Gating

Recent disclosure of high resolution crystal structures of <i>Gloeobacter violaceus</i> (GLIC) in open state and <i>Erwinia chrysanthemii</i> (ELIC) in closed state provides newer avenues to advance our knowledge and understanding of the physiologically and pharmacologically important ionotropic GABA_A ion channel. The present modeling study envisions understanding the complex molecular transitions involved in ionic conductance, which were not evident in earlier disclosed homology models. In particular, emphasis was put on understanding the structural basis of gating, gating transition from the closed to the open state on an atomic scale. Homology modeling of two different physiological states of GABA_A was carried out using their respective templates. The ability of induced fit docking in breaking the critical inter residue salt bridge (Glu155β₂ and Arg207β₂) upon endogenous GABA docking reflects the perceived side chain rearrangements that occur at the orthosteric site and consolidate the quality of the model. Biophysical calculations like electrostatic mapping, pore radius calculation, ion solvation profile, and normal-mode analysis (NMA) were undertaken to address pertinent questions like the following: How the change in state of the ion channel alters the electrostatic environment across the lumen; How accessible is the Cl^– ion in the open state and closed state; What structural changes regulate channel gating. A “Twist to Turn” global motion evinced at the quaternary level accompanied by tilting and rotation of the M2 helices along the membrane normal rationalizes the structural transition involved in gating. This perceived global motion hints toward a conserved gating mechanism among pLGIC. To paraphrase, this modeling study proves to be a reliable framework for understanding the structure function relationship of the hitherto unresolved GABA_A ion channel. The modeled structures presented herein not only reveal the structurally distinct conformational states of the GABA_A ion channel but also explain the biophysical difference between the respective states