S···O and S···N Sulfur Bonding Interactions in Protein-Ligand Complexes: Empirical Considerations and Scoring Function

Sulfur bonding interactions between organosulfur compounds and proteins were examined using crystal structures deposited to-date in the PDB. The data was analyzed as a function of sulfur-σ-hole-bonding (i.e., sulfur bonds) to main chain Lewis bases, viz. oxygen and nitrogen atoms of the backbone amide linkages. The analyses also included an examination of sulfur bonding to side chain Lewis bases (O, N, and S) and to the "non-classical" Lewis bases present in electron-rich aromatic amino acids as-well-as to donor-acceptor bond angle distributions. The interactions analyzed included those restricted to the sum of van der Waals radii of the respective atoms or to a distance of 4 Å. The surveyed data revealed that sulfur bonding tendencies (C-S-C bond angles) were impacted not only by steric effects but perhaps also by enthalpic features present in both the donor and acceptor participants. This knowledge is not only of fundamental interest but is also important in terms of materials and drug-design involving moieties incorporating the sulfur atom. Additionally, a new empirical scoring function was developed to address the anisotropy of sulfur in protein-ligand interactions. This newly developed scoring function is incorporated into AutoDock Vina molecular docking program and is valuable for modeling and drug design.

[1]  Lu Yunxiang,et al.  Theoretical and crystallographic data investigations of noncovalent S···O interactions , 2011 .

[2]  M. Iwaoka,et al.  Mining and Structural Characterization of S···X Chalcogen Bonds in Protein Database , 2015 .

[3]  A. Frontera,et al.  Aerogen Bonding Interaction: A New Supramolecular Force? , 2015, Angewandte Chemie.

[4]  M. Narayan,et al.  Identification of Novel Nitrosative Stress Inhibitors through Virtual Screening and Experimental Evaluation , 2012, Molecular informatics.

[5]  J. Murray,et al.  σ-hole bonding: molecules containing group VI atoms , 2007 .

[6]  Shuji Tomoda,et al.  Weak Nonbonded S···X (X = O, N, and S) Interactions in Proteins. Statistical and Theoretical Studies. , 2002 .

[7]  Peter Politzer,et al.  Halogen bonding and the design of new materials: organic bromides, chlorides and perhaps even fluorides as donors , 2007, Journal of molecular modeling.

[8]  Shuji Tomoda,et al.  Statistical and theoretical investigations on the directionality of nonbonded S...O interactions. Implications for molecular design and protein engineering. , 2002, Journal of the American Chemical Society.

[9]  Arthur J. Olson,et al.  AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading , 2009, J. Comput. Chem..

[10]  J. Murray,et al.  Simultaneous σ-hole and hydrogen bonding by sulfur- and selenium-containing heterocycles , 2008 .

[11]  Peter Politzer,et al.  An overview of halogen bonding , 2007, Journal of molecular modeling.

[12]  Peter Politzer,et al.  Surface electrostatic potentials of halogenated methanes as indicators of directional intermolecular interactions , 1992 .

[13]  R. Stewart.  Valence Structure from X‐Ray Diffraction Data: Physical Properties , 1972 .

[14]  Suman Sirimulla,et al.  AutoDock VinaXB: implementation of XBSF, new empirical halogen bond scoring function, into AutoDock Vina , 2016, Journal of Cheminformatics.

[15]  Peter Politzer,et al.  Expansion of the σ-hole concept , 2009, Journal of molecular modeling.

[16]  J. Murray,et al.  Why are dimethyl sulfoxide and dimethyl sulfone such good solvents? , 2008, Journal of molecular modeling.

[17]  Stereochemistry of the Interaction between Methionine Sulfur and the Protein Core , 1999, Biological chemistry.

[18]  Pinak Chakrabarti,et al.  Disulfide bonds, their stereospecific environment and conservation in protein structures. , 2004, Protein engineering, design & selection : PEDS.

[19]  T. Das,et al.  Withaferin-A suppress AKT induced tumor growth in colorectal cancer cells , 2016, Oncotarget.

[20]  Timothy Clark,et al.  Directional Weak Intermolecular Interactions: σ-Hole Bonding , 2010 .

[21]  M. Iwaoka,et al.  Statistical Characterization of Nonbonded S···O Interactions in Proteins , 2001 .

[22]  Peter Politzer,et al.  Chemical Applications of Atomic and Molecular Electrostatic Potentials: "Reactivity, Structure, Scattering, And Energetics Of Organic, Inorganic, And Biological Systems" , 2013 .

[23]  Himansu S. Biswal,et al.  Nature of the N-H...S hydrogen bond. , 2009, The journal of physical chemistry. A.

[24]  Patric Schyman,et al.  Treatment of Halogen Bonding in the OPLS-AA Force Field; Application to Potent Anti-HIV Agents. , 2012, Journal of chemical theory and computation.

[25]  H. Kjaergaard,et al.  Similar strength of the NH···O and NH···S hydrogen bonds in binary complexes. , 2014, The journal of physical chemistry. A.

[26]  Suman Sirimulla,et al.  Halogen Interactions in Protein-Ligand Complexes: Implications of Halogen Bonding for Rational Drug Design , 2013, J. Chem. Inf. Model..

[27]  G. Petsko,et al.  The crystal structure of benzoylformate decarboxylase at 1.6 A resolution: diversity of catalytic residues in thiamin diphosphate-dependent enzymes. , 1998, Biochemistry.

[28]  Peter Politzer,et al.  A predicted new type of directional noncovalent interaction , 2007 .

[29]  Kristin L. Andrews,et al.  Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint. , 2015, Journal of medicinal chemistry.

[30]  Himansu S. Biswal,et al.  Strength of NH···S Hydrogen Bonds in Methionine Residues Revealed by Gas-Phase IR/UV Spectroscopy. , 2012, The journal of physical chemistry letters.

[31]  B. Beno,et al.  A Survey of the Role of Noncovalent Sulfur Interactions in Drug Design. , 2015, Journal of medicinal chemistry.

[32]  M. Iwaoka,et al.  Possible roles of S···O and S···N interactions in the functions and evolution of phospholipase A2 , 2006, Biophysics.

[33]  Timothy Clark,et al.  Halogen bonding: an electrostatically-driven highly directional noncovalent interaction. , 2010, Physical chemistry chemical physics : PCCP.

[34]  M. Scholfield,et al.  Halogen bonding (X‐bonding): A biological perspective , 2013, Protein science : a publication of the Protein Society.

[35]  Eric Westhof,et al.  Halogen bonds in biological molecules. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Enade Perdana Istyastono,et al.  PyPLIF: Python-based Protein-Ligand Interaction Fingerprinting , 2013, Bioinformation.

[37]  Tao Lu,et al.  Intermolecular Sulfur···Oxygen Interactions: Theoretical and Statistical Investigations , 2015, J. Chem. Inf. Model..

[38]  Timothy Clark,et al.  Halogen bonding: the σ-hole , 2007 .

[39]  Pavel Hobza,et al.  Blue shifts vs red shifts in σ-hole bonding , 2008, Journal of molecular modeling.

[40]  Weiliang Zhu,et al.  Halogen bonding--a novel interaction for rational drug design? , 2009, Journal of medicinal chemistry.

[41]  Henry A. Bent,et al.  Structural chemistry of donor-acceptor interactions , 1968 .

[42]  Steven H. Liang,et al.  Sulfur Containing Scaffolds in Drugs: Synthesis and Application in Medicinal Chemistry. , 2016, Current topics in medicinal chemistry.

[43]  A. Joerger,et al.  Principles and applications of halogen bonding in medicinal chemistry and chemical biology. , 2013, Journal of medicinal chemistry.

[44]  Timothy Clark,et al.  Halogen bonding and other σ-hole interactions: a perspective. , 2013, Physical chemistry chemical physics : PCCP.

[45]  S. Suman,et al.  Targeting aberrant expression of Notch‐1 in ALDH+ cancer stem cells in breast cancer , 2017, Molecular carcinogenesis.