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  • 1
    ISSN: 1573-4951
    Keywords: Molecular mechanics ; Atomic charge ; Intermolecular interaction ; Extended electron distribution ; Atom-centred charges
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Extended electron distributions (XEDs) have been used to simulate the formation of complexes by intermolecular interaction via: (i) aromatic stacking; and (ii) hydrogen bonding. The results qualitatively reproduce experimental observations. In contrast, atom-centred partial charges fail to reproduce highly hydrogen-bonded systems, but make little difference in cases where interactions are driven largely by van der Waals forces. The dielectric constant used in the Coulombic term has been shown to be significant in defining the type and properties of these interactions when XEDs are employed. Some consideration has been given to solvation and entropy effects.
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  • 2
    ISSN: 1573-4951
    Keywords: Structure-based drug design ; Thrombin ; Combinatorial chemistry ; Functional group ; CCLD ; Electrostatic screening ; Desolvation ; Finite-difference Poisson-Boltzmann technique
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary A new method is presented for computer-aided ligand design by combinatorial selection of fragments that bind favorably to a macromolecular target of known three-dimensional structure. Firstly, the multiple-copy simultaneous-search procedure (MCSS) is used to exhaustively search for optimal positions and orientations of functional groups on the surface of the macromolecule (enzyme or receptor fragment). The MCSS minima are then sorted according to an approximated binding free energy, whose solvation component is expressed as a sum of separate electrostatic and nonpolar contributions. The electrostatic solvation energy is calculated by the numerical solution of the linearized Poisson-Boltzmann equation, while the nonpolar contribution to the binding free energy is assumed to be proportional to the loss in solvent-accessible surface area. The program developed for computational combinatorial ligand design (CCLD) allows the fast and automatic generation of a multitude of highly diverse compounds, by connecting in a combinatorial fashion the functional groups in their minimized positions. The fragments are linked as two atoms may be either fused, or connected by a covalent bond or a small linker unit. To avoid the combinatorial explosion problem, pruning of the growing ligand is performed according to the average value of the approximated binding free energy of its fragments. The method is illustrated here by constructing candidate ligands for the active site of human α-thrombin. The MCSS minima with favorable binding free energy reproduce the interaction patterns of known inhibitors. Starting from these fragments, CCLD generates a set of compounds that are closely related to high-affinity thrombin inhibitors. In addition, putative ligands with novel binding motifs are suggested. Probable implications of the MCSS-CCLD approach for the evolving scenario of drug discovery are discussed.
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  • 3
    ISSN: 1573-4951
    Keywords: Molecular docking ; Protein-ligand interaction ; Scoring function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Exploitation of protein structures for potential drug leads by molecular docking is critically dependent on methods for scoring putative protein-ligand interactions. An ideal function for scoring must exhibit predictive accuracy and high computational speed, and must be tolerant of variations in the relative protein-ligand molecular alignment and conformation. This paper describes the development of an empirically derived scoring function, based on the binding affinities of protein-ligand complexes coupled with their crystallographically determined structures. The function's primary terms involve hydrophobic and polar complementarity, with additional terms for entropic and solvation effects. The issue of alignment/conformation dependence was solved by constructing a continuous differentiable nonlinear function with the requirement that maxima in ligand conformation/alignment space corresponded closely to crystallographically determined structures. The expected error in the predicted affinity based on cross-validation was 1.0 log unit. The function is sufficiently fast and accurate to serve as the objective function of a molecular-docking search engine. The function is particularly well suited to the docking problem, since it has spatially narrow maxima that are broadly accessible via gradient descent.
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  • 4
    ISSN: 1573-4951
    Keywords: Cu,Zn superoxide dismutase ; Molecular dynamics ; Active site asymmetry ; Atomic displacement covariance matrix
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Molecular dynamics (MD) simulations of 100 ps have been carried out to study the active-site behaviour of the Cu,Zn superoxide dismutase dimer (SOD) in water. The active site of each subunit was monitored during the whole simulation by calculating the distances between functional residues and the catalytic copper. The results indicate that charge orientation is maintained at each active site but the solvent accessibility varies. Analysis of the MD simulation, carried out by using the atomic displacement covariance matrix, has shown a different intra-subunit correlation pattern for the two monomers and the presence of inter-subunit correlations. The MD simulation presented here indicates an asymmetry in the two active sites and different dynamic behaviour of the two SOD subunits.
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  • 5
    ISSN: 1573-4951
    Keywords: G-protein-coupled receptor ; Hartree-Fock calculations ; Histamine H2 receptor ; Molecular mechanics ; Receptor models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary In the first part (pp. 461–478 in this issue) of this study regarding the histamine H2 receptor agonistic binding site, the best possible interactions of histamine with an α-helical oligopeptide, mimicking a part of the fifth transmembrane α-helical domain (TM5) of the histamine H2 receptor, were considered. It was established that histamine can only bind via two H-bonds with a pure α-helical TM5, when the binding site consists of Tyr182/Asp186 and not of the Asp186/Thr190 couple. In this second part, two particular three-dimensional models of G-protein-coupled receptors previously reported in the literature are compared in relation to agonist binding at the histamine H2 receptor. The differences between these two receptor models are discussed in relation to the general benefits and limitations of such receptor models. Also the pros and cons of simplifying receptor models to a relatively easy-to-deal-with oligopeptide for mimicking agonistic binding to an agonistic binding site are addressed. Within complete receptor models, the simultaneous interaction of histamine with both TM3 and TM5 can be analysed. The earlier suggested three-point interaction of histamine with the histamine H2 receptor can be explored. Our results demonstrate that a three-point interaction cannot be established for the Asp98/Asp186/Thr190 binding site in either of the investigated receptor models, whereas histamine can form three H-bonds in case the agonistic binding site is constituted by the Asp98/Tyr182/Asp186 triplet. Furthermore this latter triplet is seen to be able to accommodate a series of substituted histamine analogues with known histamine H2 agonistic activity as well.
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  • 6
    ISSN: 1573-4951
    Keywords: α-helical model system ; Conformational analysis ; Counterpoise method ; Hartree-Fock calculations ; Histamine H2 receptor ; Molecular mechanics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Mutation studies on the histamine H2 receptor were reported by Gantz et al. [J. Biol. Chem., 267 (1992) 20840], which indicate that both the mutation of the fifth transmembrane Asp186 (to Ala186) alone or in combination with Thr190 (to Ala190) maintained, albeit partially, the cAMP response to histamine. Recently, we have shown that histamine binds to the histamine H2 receptor as a monocation in its proximal tautomeric form, and, moreover, we suggested that a proton is donated from the receptor towards the tele-position of the agonist, thereby triggering the biological effect [Nederkoorn et al., J. Mol. Graph., 12 (1994) 242; Eriks et al., Mol. Pharmacol., 44 (1993) 886]. These findings result in a close resemblance with the catalytic triad (consisting of Ser, His and Asp) found in serine proteases. Thr190 resembles a triad's serine residue closely, and could also act as a proton donor. However, the mutation of Thr190 to Ala190 — the latter is unable to function as a proton donor — does not completely abolish the agonistic cAMP response. At the fifth transmembrane α-helix of the histamine H2 receptor near the extracellular surface, another amino acid is present, i.e. Tyr182, so an alternative couple of amino acids, Tyr182 and Asp186, could constitute the histamine binding site at the fifth α-helix instead of the (mutated) couple Asp186 and Thr190. In the first part of our present study, this hypothesis is investigated with the aid of an oligopeptide with an α-helical backbone, which represents a part of the fifth transmembrane helix. Both molecular mechanics and ab initio data lead to the conclusion that the Tyr182/Asp186 couple is most likely to act as the binding site for the imidazole ring present in histamine.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    ISSN: 1573-4951
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
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  • 8
    ISSN: 1573-4951
    Keywords: p-Benzoquinone ; p-Benzoquinone imine ; Redox capacity ; Redox cycling ; 5-Iminodaunomycin ; Anthracyclines ; Relative reactivity ; Reducibility ; Oxidizability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The redox capacities of p-benzoquinone (I) and its analogs p-benzoquinone imine (VI) and p-benzoquinone diimine (XI) as the simplest model systems for the biochemically important quinone site of the pharmacophores of the anthracyclines has been investigated by AM1 semi-empirical and ab initio methods. The reductive activation of the parent (Q) model systems to their various redox states (quinone radical anion (% MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGaaeyuamaaCa% aaleqabaGabeylayaazaaaaaaa!37BD!\[{\text{Q}}^{{\text{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } }}} \]), semiquinone (QH⋅), semiquinone anion (QH-) and hydroquinone (QH2)), the internal geometrical reorganization and the redox capacities of the redox states have been examined by using energy-partitioning analysis, reaction enthalpies/energies for electron and proton attachments, adiabatic ionization potentials (IPad) and electron affinities (EAad), adiabatic electronegativities (Xad), dipole moments, electrostatic potentials and spin-density surfaces. EAad data and results of energy-partitioning analysis suggest that the one-electron Q to % MathType!MTEF!2!1!+-% feaafeart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaGaaeyuamaaCa% aaleqabaGabeylayaazaaaaaaa!37BD!\[{\text{Q}}^{{\text{\underset{\raise0.3em\hbox{$\smash{\scriptscriptstyle\cdot}$}}{ - } }}} \] reducibility of VI is diminished when compared to that of I. The data also predict that reduction to QH⋅, QH- and QH2 is more favorable in VI (cf. I). Deprotonation enthalpy/energy calculations predict that the oxidizability of the reduced forms of VI is diminished when compared to I. Overall, the calculations suggest that the redox cycling of VI should be diminished if deprotonation is the first step of the autoxidation of the reduced forms. The results suggest that the electron affinity of Q and deprotonation of the reduced forms (e.g., QH⋅) may play important roles in the redox cycling of the anthracyclines. It is further suggested that these same factors are probably responsible for the reduced toxicity of 5-iminodaunomycin, which consists of VI as part of its pharmacophore. A comparison of the AM1 results with ab initio results suggests that the AM1 method is capable of predicting trends in redox capacity, nucleophilicity, electrophilicity and electron affinity in the systems investigated.
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  • 9
    ISSN: 1573-4951
    Keywords: Combinatorial chemistry ; Library screening ; Ligand-protein binding ; Molecular similarity ; Molecular shape ; Scoring function
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary This paper describes a method for selecting a small, highly diverse subset from a large pool of molecules. The method has been employed in the design of combinatorial synthetic libraries for use in high-throughput screening for pharmaceutical lead generation. It computes diversity in terms of the main factors relevant to ligand-protein binding, namely the three-dimensional arrangement of steric bulk and of polar functionalities and molecular entropy. The method was used to select a set of 20 carboxylates suitable for use as side-chain precursors in a polyamine-based library. The method depends on estimates of various physical-chemical parameters involved in ligand-protein binding; experiments examined the sensitivity of the method to these parameters. This paper compares the diversity of randomly and rationally selected side-chain sets; the results suggest that careful design of synthetic combinatorial libraries may increase their effectiveness several-fold.
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  • 10
    ISSN: 1573-4951
    Keywords: CoMFA ; Electrotopological state ; QSAR
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary The derivation of a new 3D QSAR field based on the electrotopological state (E-state) formalism is described. A complementary index and its associated field, the HE-state, describing the polarity of hydrogens is also defined. These new fields are constructed from a nonempirical index that incorporates electronegativity, the inductive influence of neighboring atoms, and the topological state into a single atomistic descriptor. The classic CoMFA steroid test data set was examined with models incorporating the E-state and HE-state fields alone and in combination with steric, electrostatic and hydropathic fields. The single best model was the E-state/HE-state combination with q2=0.803 (three components) and r2=0.979. Using the E-state and/or HE-state fields with other fields consistently produced models with improved statistics, where the E-state fields provided a significant, if not dominant, contribution.
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