Molecular Docking Using the Molecular Lipophilicity Potential as Hydrophobic Descriptor: Impact on GOLD Docking Performance

GOLD is a molecular docking software widely used in drug design. In the initial steps of docking, it creates a list of hydrophobic fitting points inside protein cavities that steer the positioning of ligand hydrophobic moieties. These points are generated based on the Lennard-Jones potential between a carbon probe and each atom of the residues delimitating the binding site. To thoroughly describe hydrophobic regions in protein pockets and properly guide ligand hydrophobic moieties toward favorable areas, an in-house tool, the MLP filter, was developed and herein applied. This strategy only retains GOLD hydrophobic fitting points that match the rigorous definition of hydrophobicity given by the molecular lipophilicity potential (MLP), a molecular interaction field that relies on an atomic fragmental system based on 1-octanol/water experimental partition coefficients (log <i>P</i>_oct). MLP computations in the binding sites of crystallographic protein structures revealed that a significant number of points considered hydrophobic by GOLD were actually polar according to the MLP definition of hydrophobicity. To examine the impact of this new tool, ligand–protein complexes from the Astex Diverse Set and the PDB bind core database were redocked with and without the use of the MLP filter. Reliable docking results were obtained by using the MLP filter that increased the quality of docking in nonpolar cavities and outperformed the standard GOLD docking approach

Molecular dynamics of zinc-finger ubiquitin binding domains: a comparative study of histone deacetylase 6 and ubiquitin-specific protease 5

<p>HDAC6 is a unique cytoplasmic histone deacetylase characterized by two deacetylase domains, and by a zinc-finger ubiquitin binding domain (ZnF-UBP) able to recognize ubiquitin (Ub). The latter has recently been demonstrated to be involved in the progression of neurodegenerative diseases and in mediating infection by the influenza A virus. Nowadays, understanding the dynamic and energetic features of HDAC6 ZnF-UBP-Ub recognition is considered as a crucial step for the conception of HDAC6 potential modulators. In this study, the atomic, solvent-related, and thermodynamic features behind HDAC6 ZnF-UBP-Ub recognition have been analyzed through molecular dynamics simulations. The behavior was then compared to the prototypical ZnF-UBP from ubiquitin-specific protease 5 (USP5) in order to spot relevant differences useful for selective drug design. Principal component analysis highlighted flapping motions of the L2A loop which were lowered down upon Ub binding in both systems. While polar and nonpolar interactions involving Ub G75 and G76 residues were also common features stabilizing both complexes, salt bridges showed a different pattern, more significant in HDAC6 ZnF-UBP-Ub, whose energetic contribution in USP5 ZnF-UBP-Ub was compensated by the presence of a more stable bridging water molecule. Whereas molecular mechanics/Poisson–Boltzmann surface area (MM-PBSA) free energies of binding were comparable for both systems, in agreement with experiments, computational alanine scanning and free energy decomposition data revealed that HDAC6 E1141 and D1178 are potential hotspots for the design of selective HDAC6 modulators.</p

Sequence alignment between TcSir2rp1 and hSIRT2.

<p>Conserved amino acids are highlighted in yellow.</p

Molecular docking results from the virtual screening of the productive conformational state of TcSIR2rp1.

<p>(A) Anacardic acid best-ranked docking pose in the TcSIR2rp1 productive form. (B) Aculeatin D best-ranked docking pose in the TcSIR2rp1 productive form. (C) 16-acetoxy-11-hydroxyoctadeca-17-ene-12,14-diynylethanoate best-ranked docking pose in the TcSIR2rp1 productive form. (D) Vismione D best-ranked docking pose in the TcSIR2rp1 productive form. Protein structures are represented as dark pink ribbons. Amino acids participating in protein-ligand interactions are indicated bylight gray sticks. Ligands are represented in capped sticks and are colored in orange. GRID surface are also reported in the active site pockets and are colored as yellow, blue and red to highlight the hydrophobic, electron-donor and electron-acceptor properties, respectively.</p

Superimposition of ten NAD⁺ docking poses in the TcSIR2rp1 productive (A) and non-productive (B) forms.

<p>NAD⁺ molecules are represented in brown-capped sticks. Protein structures are represented as ribbons and colored in dark pink and green representing the TcSIR2rp1 productive and non-productive form, respectively. Pocket surfaces were generated with MOE (MOE 2012.10; Chemical Computing Group, Montreal, Canada) and are colored in gray.</p

PLP scores for the anti-trypanosomal compounds docked into <i>Tc</i>SIR2rp1 and <i>Tc</i>SIR2rp3 productive forms.

<p>The compounds selected from the virtual screening for structural inspections are reported in bold.</p

Synthesis and Biological Evaluation of Direct Thrombin Inhibitors Bearing 4‑(Piperidin-1-yl)pyridine at the P1 Position with Potent Anticoagulant Activity

The design and synthesis of a new class of nonpeptide direct thrombin inhibitors, built on the structure of 1-(pyridin-4-yl)­piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (<b>6</b>) showing poor thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure–activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound <b>13b</b>, which showed excellent fIIa inhibition (<i>K</i>_i = 6 nM), weak anti-Xa activity (<i>K</i>_i = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound <b>13b</b> showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), <b>13b</b> demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg^–1), with a significant 43% prolongation of the activated partial thromboplastin time (aPTT), over controls (<i>P</i> < 0.05)

Structure-Based Design and Optimization of Multitarget-Directed 2<i>H</i>‑Chromen-2-one Derivatives as Potent Inhibitors of Monoamine Oxidase B and Cholinesterases

The multifactorial nature of Alzheimer’s disease calls for the development of multitarget agents addressing key pathogenic processes. To this end, by following a docking-assisted hybridization strategy, a number of aminocoumarins were designed, prepared, and tested as monoamine oxidases (MAOs) and acetyl- and butyryl-cholinesterase (AChE and BChE) inhibitors. Highly flexible <i>N</i>-benzyl-<i>N</i>-alkyloxy coumarins <b>2</b>–<b>12</b> showed good inhibitory activities at MAO-B, AChE, and BChE but low selectivity. More rigid inhibitors, bearing <i>meta</i>- and <i>para</i>-xylyl linkers, displayed good inhibitory activities and high MAO-B selectivity. Compounds <b>21</b>, <b>24</b>, <b>37</b>, and <b>39</b>, the last two featuring an improved hydrophilic/lipophilic balance, exhibited excellent activity profiles with nanomolar inhibitory potency toward hMAO-B, high hMAO-B over hMAO-A selectivity and submicromolar potency at hAChE. Cell-based assays of BBB permeation, neurotoxicity, and neuroprotection supported the potential of compound <b>37</b> as a BBB-permeant neuroprotective agent against H₂O₂-induced oxidative stress with poor interaction as P-gp substrate and very low cytotoxicity