A fast protein-ligand docking algorithm based on hydrogen bond matching and surface shape complementarity

With the rapid development of structural determination of target proteins for human diseases, high throughout virtual screening based drug discovery is gaining popularity gradually. In this paper, a fast docking algorithm (H-DOCK) based on hydrogen bond matching and surface shape complementarity was developed. In H-DOCK, firstly a divide-and-conquer strategy based enumeration approach is applied to rank the intermolecular modes between protein and ligand by maximizing their hydrogen bonds matching, then each docked conformation of the ligand is calculated according to the matched hydrogen bonding geometry, finally a simple but effective scoring function reflecting mainly the van der Waals interaction is used to evaluate the docked conformations of the ligand. H-DOCK is tested for rigid ligand docking and flexible one, the latter is implemented by repeating rigid docking for multiple conformations of a small molecule and ranking all together. For rigid ligands, H-DOCK was tested on a set of 271 complexes where there is at least one intermolecular hydrogen bond, and H-DOCK achieved success rate (RMSD<2.0?Å) of 91.1%. For flexible ligands, H-DOCK was tested on another set of 93 complexes, where each case was a conformation ensemble containing native ligand conformation as well as 100 decoy ones generated by AutoDock [1], and the success rate reached 81.7%. The high success rate of H-DOCK indicates that the hydrogen bonding and steric hindrance can grasp the key interaction between protein and ligand. H-DOCK is quite efficient compared with the conventional docking algorithms, and it takes only about 0.14 seconds for a rigid ligand docking and about 8.25 seconds for a flexible one on average. According to the preliminary docking results, it implies that H-DOCK can be potentially used for large scale virtual screening as a pre-filter for a more accurate but less efficient docking algorithm.     

Spectroscopic and molecular docking investigation of polynucleotides and DNA binding affinity to Nile blue dye

We used UV-vis absorption spectroscopy, fluorescence spectrophotometry and molecular docking calculations to investigate intermolecular interaction between the cationic dye, Nile blue (NB), and synthetic polynucleotides, poly(A-T), poly(G-C) and calf thymus DNA (Ct-DNA) at physiological pH. Strong hypsochromic absorbance and fluorescence quenching were observed that showed strong binding of NB to these polynucleotides and DNA. The binding affinity values derived from maximum absorption of the spectra of NB bound to various polynucleotides and Ct-DNA concentrations suggests that NB exhibits greater binding affinity to poly(G-C) than to poly(A-T). The thermodynamic parameters suggested that hydrogen bonds and van der Waals forces might play a major role in the binding of NB to DNA. The molecular docking results suggested that NB was an intercalator of the stacked base pairs of Ct-DNA.     

Probing the binding interaction of AKR with human serum albumin by multiple fluorescence spectroscopy and molecular modeling

Human serum albumin (HSA) is the major transport protein affording endogenous and exogenous substances in plasma. It can affect the behavior and efficacy of chemicals in vivo through the binding interaction. AKR (3-O-α-l-arabinofuranosyl-kaempferol-7-O-α-l-rhamnopyranoside) is a flavonoid diglycoside with modulation of estrogen receptors (ERs). Herein, we investigated the binding interaction between AKR and HSA by multiple fluorescence spectroscopy and molecular modeling. As a result, AKR specifically binds in site I of HSA through hydrogen bonds, van der Waals force, and electrostatic interaction. The formation of AKR–HSA complex in binding process is spontaneously exothermic and leads to the static fluorescence quenching through affecting the microenvironment around the fluorophores. The complex also affects the backbone of HSA and makes AKR access to fluorophores. Molecular modeling gives the visualization of the interaction between AKR and HSA as well as ERs. The affinity of AKR with HSA is higher than the competitive site marker Warfarin. In addition, docking studies reveal the binding interaction of AKR with ERs through hydrogen bonds, van der Waals force, hydrophobic, and electrostatic interactions. And AKR is more favorable to ERβ. These results unravel the binding interaction of AKR with HSA and mechanism as an ERs modulator.     

Binding of fexofenadine hydrochloride to bovine serum albumin: structural considerations by spectroscopic techniques and molecular docking

The binding interaction of peripheral H₁ receptor antagonist drug, fexofenadine hydrochloride to bovine serum albumin (BSA) is investigated by fluorescence spectroscopy in combination with UV-absorption spectroscopy under physiological conditions. The Stern–Volmer plots at different temperatures and the steady state fluorescence suggested a static type of interaction between fexofenadine and BSA. Binding constants were determined to provide a measure of the binding affinity between fexofenadine and BSA. It was found that BSA has one binding site for fexofenadine. On the basis of the competitive site marker experiments and thermodynamic results, it was considered that fexofenadine was primarily bound to the site I of BSA mainly by hydrogen bond and van der Waals force. Utilising Förster resonance energy transfer the distance, r between the donor, BSA and acceptor fexofenadine was obtained. Furthermore, the results of circular dichroism and synchronous fluorescence spectrum indicated that the secondary structure of BSA was changed in the presence of fexofenadine. Molecular docking was applied to further define the interaction of fexofenadine with BSA.     

Resolution of sertraline with (R)-mandelic acid: chiral discrimination mechanism study

The chiral discrimination mechanism in the resolution of sertraline with mandelic acid was investigated by examining the weak intermolecular interactions (such as hydrogen bond, CH/π, and van der Waals interactions) and molecular packing difference in crystal structures of the resulting diastereomeric salts. A new one-dimensional chain-like hydrogen-bonding network and unique supramolecular packing mode are disclosed. The investigation demonstrated that stable hydrogen-bonding pattern, herringbone-like arrangement of aromatic rings, and planar boundary surface in the hydrophobic region are the three most important structural characteristics expected in less soluble diastereomeric salts. The existence and magnitude of hydrogen bond, CH/π interaction, and van der Waals interaction related to three characteristic structures, determine the stability of diastereomeric salt. The hydrogen bond is not necessarily the dominant factor while the synergy and optimization of all weak intermolecular interactions attribute to the chiral recognition.     

Energetics of complex formation of the DNA hairpin structure d(GCGAAGC) with aromatic ligands

The energy contributions of various physical interactions to the total Gibbs energy of complex formation of the biologically important DNA hairpin d(GCGAAGC) with aromatic antitumor antibiotics daunomycin and novantron and the mutagens ethidium and proflavine have been calculated. It has been shown that the relatively small value of the total energy of binding of the ligands to the hairpin is the sum of components great in absolute value and different in sign. The contributions of van der Waals interactions and both intra- and intermolecular hydrogen bonds and bonds with aqueous environment have been studied. According to the calculations, the hydrophobic and van der Waals components are energetically favorable in complex formation of the ligands with the DNA pairpin d(GCGAAGC), whereas the electrostatic (with consideration of hydrogen bonds) and entropic components are unfavorable.     

Energetics of complex formation of the dna hairpin structure d(GCGAAGC) with aromatic ligands

The energy contributions of various physical interactions to the total Gibbs energy of complex formation of the biologically important DNA hairpin d(GCGAAGC) with aromatic antitumor antibiotics daunomycin and novantrone and mutagens ethidium bromide and proflavin have been calculated. It has been shown that the relatively small value of the total energy of binding of the ligands to the hairpin is the sum of components great in absolute value and different in sign. The contributions of van der Waals interactions and both intra- and intermolecular hydrogen bonds and bonds with aqueous environment have been studied. According to the calculations, the hydrophobic and van der Waals components are energetically favorable in complex formation of the ligands with the hairpin d(GCGAAGC), whereas the electrostatic (with consideration of hydrogen bonds) and entropic components are unfavorable.     

DNA binding properties of novel distamycin analogs that lack the leading amide unit at the N-terminus

First examples of distamycin (Dst) analogs which lack hydrogen bond donor or acceptor groups at the N-terminus have been synthesized. The first molecule of this series, which is a bispyrrole peptide, did not exhibit any detectable binding with double-stranded (ds) DNA. However, all other analogs did bind strongly to AT-rich sequences of ds-DNA, with the binding affinities increasing as a function of the number of repeating pyrrole carboxamide units. These results imply that a hydrogen bond donor or acceptor atom per se at the N-terminus is not a prerequisite for DNA binding in the case of pyrrole carboxamide-based Dst analogs. However, in the absence of H-bond donor or acceptor at the N-terminus, a minimum of three pyrrole carboxamide units is necessary for the onset of DNA binding. Beyond this minimum number, the binding affinity increases as a function of the number of pyrrole units, as a result of the greater availability of hydrogen bonding and van der Waals surface. Experiments with poly[d(G-C)] have shown that the presence of the N-terminus formamide group is not inevitable for GC binding of this class of molecules. The observation that the N-terminus formamide unit can be dispensed with suggests that these molecules, which are much easier to synthesize and functionalize, can be used in place of the conventional analogs of distamycin for the development of novel minor groove binders with extended sequence recognition properties.     

Binding of a bcl-2 Family Inhibitor to Bovine Serum Albumin: Fluorescence Quenching and Molecular Docking Study

Both fluorescence spectroscopic and molecular docking methods were used to investigate the interaction between bovine serum albumin (BSA) and a known Bcl-xl/Bcl-2 inhibitor HA 14-1. Based on the spectral overlap between the emission of BSA and absorption of HA 14-1, Forster energy transfer was proposed to be the possible quenching mechanism. The Stern-Volmer constants are 2.49 x 104, 2.04x 104 and 0.90 x 104 M-1 at 293, 303 and 318 K, respectively, indicating that a static quenching process dominates. Thermodynamic parameters were further obtained. The derived negative Δ H (-27.51 kJ mol-1) and Δ S (-11.11 J mol-1K-1) values suggest hydrogen bond interaction and van der Waals force are the main binding force. The docking study was performed on BSA model. According to the docking score and the number of hydrogen bonds, the potential binding site for HA 14-1 is proposed to be the site IIA, also known as drug site 1.     

Molecular interaction of manganese based carbon monoxide releasing molecule (MnCORM) with human serum albumin (HSA)

In the present study, the interaction between the HSA and MnCORM in vitro under physiological conditions, was investigated through ultraviolet-visible (UV-vis) absorption, fluorescence, time-resolved fluorescence, circular dichroism (CD), Fourier transform infrared (FT-IR) spectroscopic techniques and in silico molecular docking methods. Binding parameters such as the binding constant, number of binding sites and binding force were obtained from the fluorescence data. Thermodynamic interaction revealed that the reaction was spontaneous (ΔG < 0) and hydrogen bond and van der Waals interaction were primarily involved in the binding. The changes induced in the secondary structure conformation due to the MnCORM interaction were monitored using CD and FT-IR spectroscopic techniques. The results showed reduction in α-helix conformation and corresponding increase in β-sheet and unordered structures due to slight unfolding. The time-resolved fluorescence decay confirmed the static quenching mechanism of the MnCORM. The molecular docking studies revealed that the MnCORM interacted at Sudlow’s site II of domain IIIA through hydrogen bond and van der Waals interactions. In order to understand the drug distribution and elimination, studies on the drug molecule interaction with HSA are vital. Therefore, it is evident that MnCORM interacts with HSA through ground state complex formation and thus suitable for in vivo delivery.     

胡椒碱分子键合人血清白蛋白位点的表征

利用荧光光谱法、紫外光谱法并结合计算机模拟技术在分子水平上研究了胡椒碱与人血清白蛋白(human serum albumin HSA)的键合作用.同步荧光及紫外光谱图表明,胡椒碱对HSA微环境有影响.位点竞争试验证明,胡椒碱分子键合在HSA的位点Ⅱ区.通过荧光光谱滴定数据求得不同温度下(300K 310K和318 K)药物与蛋白相互作用的结合常数及结合位点数.分子模拟的结果显示了胡椒碱与HSA的键合区域和键合模式,表明药物与蛋白有较强的键合作用;维持药物与蛋白质的相互作用力主要是疏水用,兼有氢键(位于氨基酸残基Arg 257,Arg 222及Arg218位).通过实验数据计算得到的热力学参数(ΔH0与ΔS0的值分别为原33.11 kJ·mol-1和原18.90 J·mol原1·K-1)确定了胡椒碱与HSA分子的相互作用力类型主要为氢键兼范德华力.     

Probing the electronic structures and properties of neutral and anionic ScSi n (0,−1) (n = 1–6) clusters using ccCA-TM and G4 theory

We apply molecular docking, molecular dynamics (MD) simulation, and binding free energy calculation to investigate and reveal the binding mechanism between five xanthine inhibitors and DPP-4. The electrostatic and van der Waals interactions of the five inhibitors with DPP-4 are analyzed and discussed. The computed binding free energies using MM-PBSA method are in qualitatively agreement with experimental inhibitory potency of five inhibitors. The hydrogen bonds of inhibitors with Ser630 and Asp663 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the key contacts with His740, Asn710, Trp629, and Tyr666 have larger contributions to the binding free energy and play important roles in distinguishing the variant bioactivity of five inhibitors.     

Interaction of colchicine with human serum albumin investigated by spectroscopic methods

We investigated the interaction between colchicine and human serum albumin (HSA) by fluorescence and UV-vis absorption spectroscopy. In the mechanism discussion, it was proved that the fluorescence quenching of HSA by colchicine is a result of the formation of colchicines-HSA complex; van der Waals interactions and hydrogen bonds play a major role in stabilizing the complex. The modified Stern-Volmer quenching constant K(a) and corresponding thermodynamic parameters deltaH, deltaG, deltaS at different temperatures were calculated. The distance r between donor (Trp214) and acceptor (colchicine) was obtained according to fluorescence resonance energy transfer (FRET).     

Investigation on the interaction between myricetin and dihydromyricetin with trypsin, α-chymotrypsin,lysozyme by spectroscopy and molecular docking methods

The interaction between myricetin and dihydromyricetin with trypsin, α-chymotrypsin and lysozyme was investigated using multispectral and molecular docking methods. The results of fluorescence quenching revealed that myricetin and dihydromyricetin could quench the intrinsic fluorescence of three different proteinases through a static quenching procedure. The binding constant and number of binding sites at different temperatures were measured. The thermodynamic parameters obtained at different temperatures showed van der Waals interactions and hydrogen bonds played the main roles in the interaction of myricetin with trypsin and lysozyme, hydrophobic force was dominant both in myricetin with α-chymotrypsin interaction and dihydromyricetin with trypsin and lysozyme interaction, as for the electrostatic forces, it was mainly the driving force in dihydromyricetin binding to α-chymotrypsin. There was non-radiative energy transfer between three proteinases and myricetin or dihydromyricetin with high probability. The microenvironment of trypsin, α-chymotrypsin and lysozyme is changed. The docking studies revealed that myricetin and dihydromyricetin entered the hydrophobic cavity of three proteinases and formed hydrogen bonds. The binding affinity of myricetin or dihydromyricetin is different with the trypsin, α-chymotrypsin and lysozyme due to the different molecular structure.     

The Mu repressor-DNA complex contains an immobilized 'wing' within the minor groove

We have determined the solution structure of the complex between the 'winged-helix' enhancer binding domain of the Mu repressor protein and its cognate DNA site. The structure reveals an unusual use for the 'wing' which becomes immobilized upon DNA binding where it makes intermolecular hydrogen bond contacts deep within the minor groove. Although the wing is mobile in the absence of DNA, it partially negates the large entropic penalty associated with its burial by maintaining a small degree of structural order in the DNA-free state. Extensive contacts are also formed between the recognition helix and the DNA, which reads the major groove of a highly conserved region of the binding site through a single base-specific hydrogen bond and van der Waals contacts.     

Milk caseins as useful vehicle for delivery of dipyridamole drug

The interaction of bovine milk α- and β-caseins as an efficient drug carrier system with Dipyridamole (DIP) was investigated using spectroscopy and molecular docking studies at different temperatures (20–37 °C). FTIR, CD, and fluorescence spectroscopy methods demonstrated that α- and β-caseins interact with DIP molecule mainly via hydrophobic and hydrophilic interactions and change in secondary structure of α- and β-caseins. DIP showed a higher quenching efficiency and binding constant of α-casein than β-casein. There was only one binding site for DIP and it was located on the surface of the protein molecule. The thermodynamic parameters of calculation showed that the binding process occurs spontaneously and demonstrated that α- and β-caseins provide very good binding and entrapment to DIP via hydrogen bonds, Van der Waals forces, and hydrophobic interactions. Fluorescence resonance energy transfer, synchronous fluorescence spectroscopy, and docking study showed that DIP binds to the Trp residues of α- and β-casein molecules with short distances. Docking study showed that DIP molecule made several hydrogen bonds and van der Waals interactions with α- and β-caseins. The study of cell culture and micellar solubility of DIP demonstrated α- and β-caseins relatively the same helping in delivery of DIP. Milk α- and β-caseins are considered as a useful vehicle for the solublization and stabilization of DIP in aqueous solution at natural pH.     

Probing the binding of two fluoroquinolones to lysozyme: a combined spectroscopic and docking study

Ciprofloxacin (CPFX) and enrofloxacin (ENFX) are two of the most widely used fluoroquinolones (FQs) in human and veterinary medicines. Their occurrence in the environment has received much attention because of the potential adverse effects on humans and ecosystem functions. In this paper, we investigated the interaction mechanism between the two FQs and lysozyme by the spectroscopic and molecular docking methods. As shown by the fluorescence spectroscopy, additions of CPFX or ENFX effectively quenched the intrinsic fluorescence of lysozyme, which was attributed to the formation of a moderately strong complex. The enthalpy change (ΔH) and entropy change (ΔS) indicated that van der Waals forces and hydrogen bonds were the dominant intermolecular forces in the binding of two FQs to lysozyme. Furthermore, data obtained by UV-vis absorption, synchronous fluorescence and circular dichroism (CD) suggested that both CPFX and ENFX could lead to the conformational and some microenvironmental changes of lysozyme. Finally, the molecular docking illustrated that the two FQs had specific interactions with the residues of Trp62 and Trp63.     

Probing the binding mechanism of capecitabine to human serum albumin using spectrometric methods,molecular modeling,and chemometrics approach

Capecitabine as a prodrug of 5-Fluorouracil plays an important role in the treatment of breast and gastrointestinal cancers. Herein, in view of the importance of this drug in chemotherapy, interaction mechanism between Capecitabine (CAP) and human serum albumin (HSA) as a major transport protein in the blood circulatory system has been investigated by using a combination of spectroscopic and molecular modeling methods. The fluorescence spectroscopic results revealed that capecitabine could effectively quench the intrinsic fluorescence of HSA through a static quenching mechanism. Evaluation of the thermodynamic parameters suggested that the binding process was spontaneous while hydrogen bonds and van der Waals forces played a major role in this interaction. The value of the binding constant (K_b = 1.820 × 10⁴) suggested a moderate binding affinity between CAP and HSA which implies its easy diffusion from the circulatory system to the target tissue. The efficiency of energy transfer and the binding distance between the donor (HSA) and acceptor (CAP) were determined according to forster theory of nonradiation energy transfer as 0.410 and 4.135 nm, respectively. Furthermore, UV–Vis spectroscopic results confirmed that the interaction was occurred between HSA and CAP and caused conformational and micro-environmental changes of HSA during the interaction. Multivariate curve resolution-alternating least square (MCR-ALS) methodology as an efficient chemometric tool was used to separate the overlapped spectra of the species. The MCR-ALS result was exploited to estimate the stoichiometry of interaction and to provide concentration and structural information about HSA-CAP interactions. Molecular docking studies suggested that CAP binds mainly to the subdomain IIA of HSA, which were compatible with those obtained by experimental data. Finally, molecular dynamics simulation (MD) was performed on the best docked complex by considering the permanence and flexibility of HSA-CAP complex in the binding site. MD result showed that CAP could steadily bind to HSA in the site I based on the formation of hydrogen bond and π-π stacking interaction in addition to hydrophobic force.     

Hydrogen bonds in crystal structures of amino acids, peptides and related molecules

The results of a survey of 439 hydrogen bonds in 95 recently determined crystal structures of amino acids, peptides and related molecules suggest that the following generalizations hold true for linear (angle X-H---Y greater than 150 degrees) hydrogen bonds. (1) The charge on the acceptor group does not influence the length of a hydrogen bond. (2) For a given acceptor group, the hydrogen bond lengths increase in the order imidazolium N--H less than ammonium N-H less than guanidinium N-H; this order holds true for oxygen anion acceptor groups. Cl-ions and the uncharged oxygen of water molecules. (3) The uncharged imidazole N-H group forms shorter hydrogen than the amide N-H GROUP. (4) The carboxyl O-H groups form shorter hydrogen bonds than other hydroxyl groups. (5) The hydrogen bonds involving a halogen ion are longer than hydrogen bonds with other acceptors when corrected for their longer van der Walls radii. The observed differences between the lengths of hydrogen bonds formed by different donor and acceptor groups in amino acids and peptides, imply differences in the energetics of their formation.     

Anthracycline antibiotic arugomycin binds in both grooves of the DNA helix simultaneously: an NMR and molecular modelling study.

Perturbations to the 1H and 31P chemical shifts of DNA resonances together with twenty-four intermolecular nuclear Overhauser effects show that the anthracycline antibiotic arugomycin intercalates between the basepairs of the hexamer duplex d(5'-GCATGC)2 at the 5'-CpA and 5'-TpG binding sites. In the complex two drug molecules are bound per duplex with full retention of the dyad symmetry. Arugomycin adopts a threaded binding orientation with chains of sugars positioned in both the major and minor groove of the helix simultaneously. The complex is stabilized by hydrogen bonding, electrostatic and van der Waals interactions principally in the major groove and involving substituents on the rigidly oriented bicycloamino-glucose sugar of the antibiotic. A specific hydrogen bond is identified between the C2'-hydroxyl and the guanine N7 at the intercalation site. Together, interactions in the major groove appear to account for the intercalation specificity of arugomycin that requires both a guanine and thymine at the intercalation site. We are unable to identify any sequence specific interactions between the minor groove and the arugarose sugar (S1) which binds only weakly, through van der Walls contacts, over the d(GCA).d(TGC) trinucleotide sequence. The data indicate that the sugar chains of arugomycin are flexible and play little part in the interaction of the antibiotic with DNA. The intensity of sequential internucleotide NOEs identifies the intercalation site as being assymmetric. A family of conformers computed using restrained energy minimisation and molecular dynamics indicate that basepair buckling is a feature of the anthracycline intercalation site that may serve to maximise intermolecular van der Waals interactions by wrapping the basepairs around the antibiotic chromophore.