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  • 1
    Electronic Resource
    Electronic Resource
    Novel Zinc Protein Molecular Dynamics Simulations: Steps Toward Antiangiogenesis for Cancer Treatment (1999)
    Springer
    Journal of molecular modeling 5 (1999), S. 196-202 
    Details
    ISSN: 0948-5023
    Keywords: Keywords Force field parameters ; Endostatin ; Matrix metalloproteinases ; Carbonic anhydrase ; Carboxypeptidase A
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Angiogenesis is the formation of new blood vessels induced by tumors as a lifeline for oxygen and nutrients and as exits for spread of cancer cells. Blocking tumors′ blood supply could starve tumors thus saving cancer patients, and is termed antiangiogenesis. Matrix metalloproteinases (MMPs) are a class of proteins containing Zn2+ in the active site that cleave the constituents of the extracellular matrix and control angiogenesis. Selective inhibitors of MMPs therefore hold promise in antiangiogenesis for treating cancers, but development of such inhibitors is currently hampered by a paucity of effective computational methods for evaluating the intermolecular interactions between zinc and its coordinates and for performing nanosecond length molecular dynamics simulation of zinc proteins. Here I report an approach for simulating the four-coordinate zinc complex in proteins without use of covalent bonds or harmonic restraints applied to the zinc complex. This approach uses four cationic dummy atoms tetrahedrically placed around the zinc nucleus to mimic zinc′s 4s4p3 vacant orbitals that accommodate lone-pair electrons of the zinc coordinates thus imposing the orientational requirement for the zinc coordinates and simulating zinc′s propensity to a tetrahedral coordination geometry. It hence permits evaluating binding free energy of zinc coordinates and simulating the exchanges of zinc′s ambidentate coordinates in proteins, and is expected to expedite the search of effective angiogenesis inhibitors to combat cancers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s008940050119
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  • 2
    Electronic Resource
    Electronic Resource
    Models of Ternary Complexes for Nonpeptidic Farnesyltransferase Inhibitors: Insights into Structure-Based Screen and Design of Potential Anticancer Therapeutics (1999)
    Springer
    Journal of molecular modeling 5 (1999), S. 203-217 
    Details
    ISSN: 0948-5023
    Keywords: Keywords Antiangiogenesis ; Antiproliferation ; Docking study ; Drug design ; ras mutation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Farnesyltransferase (FT) inhibitors can repress tumor cell proliferation without substantially interfering with normal cell growth and are thus promising in cancer treatment. A detailed knowledge of how substrates and inhibitors bind to FT at the atomic level can expedite screening and rational design of improved FT inhibitors. Here we report theoretical models of the FT complexed with FPP and the potent nonpeptidic inhibitor SCH 56580 and other inhibitor-FPP-FT ternary complexes derived from the docking studies prior to any crystal structures of the FT liganded with nonpeptidic inhibitors. On the basis of these models we evaluate the roles of FPP, Zn2+ and the zinc-coordinated water molecule in inhibitor binding, and propose the structural determinants of binding of nonpeptidic FT inhibitors. Furthermore, we suggest the use of the FPP-FT binary complex as a novel and effective drug target structure for screening and rational design of improved FT inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s008940050120
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  • 3
    Electronic Resource
    Electronic Resource
    Zinc′s Exclusive Tetrahedral Coordination Governed by Its Electronic Structure (1999)
    Springer
    Journal of molecular modeling 5 (1999), S. 134-140 
    Details
    ISSN: 0948-5023
    Keywords: Keywords Zinc proteins ; Endostatin ; Farnesyltransferase ; Matrix metalloproteinases ; Zinc finger
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Zinc is a critical component of more than 300 proteins including farnesyltransferase, matrix metalloproteinases and endostatin that are involved in the front-line cancer research, and a host of proteins termed zinc fingers that mediate protein-protein and protein-nucleic acid interactions. Despite the growing appreciation of zinc in modern biology, the knowledge of zinc′s coordination nature in proteins remains controversial. It is typically assumed that Zn2+ coordinates to four to six ligands, which led to intensive debates about whether the catalysis of some zinc proteins is regulated by zinc′s four- or five-coordinate complex. Here we report the inherent uncertainty, due to the experimental resolution, in classifying zinc′s five- and six-coordinate complexes in protein crystal structures, and put forward a tetrahedral coordination concept that Zn2+ coordinates to only four ligands mainly because of its electronic structure that accommodates four pairs of electrons in its vacant 4s4p 3 orbitals. Experimental observations of five- and six-coordinate complexes were due to one or two pairs of ambidentate coordinates that exchanged over time and were averaged as bidentate coordinates. This concept advances understanding of zinc′s coordination nature in proteins and the means to study zinc proteins to unlock the secrets of Zn2+ in human biology. In particular, according to this concept, it is questionable to study zinc′s coordination in proteins with Co2+ as a surrogate of Zn2+ for spectroscopic measurements, since the former is a d7 unclosed shell divalent cation whereas the latter is a d10 closed shell divalent cation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s008940050113
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  • 4
    Electronic Resource
    Electronic Resource
    Docking Studies on the Complexed and Uncomplexed FKBP12 Structures with Bound and Unbound Ligands: An Implication of a Conformational Selection Mechanism for Binding (1997)
    Springer
    Journal of molecular modeling 3 (1997), S. 240-248 
    Details
    ISSN: 0948-5023
    Keywords: Keywords: Recognition ; induced-fit ; key-lock ; SYSDOC ; computational drug screening
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Docking of FK506, rapamycin, and L-685,818 into their receptor, FKBP12, suggests that unlike the respective structures determined by X-ray crystallography, the uncomplexed FKBP12 structures determined by NMR may not be directly usable to identify high affinity ligands by docking studies for computational drug screening. In view of the resolution of the experimentally determined structures of FKBP12 and relatively small difference of the receptor binding sites between the complexed and uncomplexed states, it is unclear if the conformational induction mechanism is relevant to the binding of FKBP12 with its ligands. Alternatively, we advocate a conformation selection mechanism fundamentally akin to a mechanism proposed by Burgen. This mechanism better explains the experimental and calculated results for the binding of FKBP12 with FK506. It emphasizes that both guest and host select their most compatible preformed conformers to effect binding, and that the observed free energy of binding is a sum of the free energy change in complexation of the two most compatible conformers and the free energy changes in conversion of the Boltzmann-weighted principal conformers to the most compatible conformers. Conceptually, this mechanism represents one physical or nonphysical path of a thermodynamic cycle that is closed by the other path represented by the conformational induction mechanism, which can also be physical or nonphysical; it provides a theoretical means to estimate the affinity of the guest to the host with the experimentally available 3D structures of the two partners.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s008940050036
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  • 5
    Electronic Resource
    Electronic Resource
    Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies (1994)
    Springer
    Journal of computer aided molecular design 8 (1994), S. 669-681 
    Details
    ISSN: 1573-4951
    Keywords: Molecular recognition ; SYSDOC ; Acetylcholinesterase inhibitors ; Alzheimer's disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary We have performed docking studies with the SYSDOC program on acetylcholinesterase (AChE) to predict the binding sites in AChE of huperzine A (HA), which is a potent and selective, reversible inhibitor of AChE. The unique aspects of our docking studies include the following: (i) Molecular flexibility of the guest and the host is taken into account, which permits both to change their conformations upon binding. (ii) The binding energy is evaluated by a sum of energies of steric, electrostatic and hydrogen bonding interactions. In the energy calculation no grid approximation is used, and all hydrogen atoms of the system are treated explicitly. (iii) The energy of cation-π interactions between the guest and the host, which is important in the binding of AChE, is included in the calculated binding energy. (iv) Docking is performed in all regions of the host's binding cavity. Based on our docking studies and the pharmacological results reported for HA and its analogs, we predict that HA binds to the bottom of the binding cavity of AChE (the gorge) with its ammonium group interacting with Trp84, Phe330, Glu199 and Asp72 (catalytic site). At the the opening of the gorge with its ammonium group partially interacting with Trp279 (peripheral site). At the catalytic site, three partially overlapping subsites of HA were identified which might provide a dynamic view of binding of HA to the catalytic site.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00124014
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  • 6
    Electronic Resource
    Electronic Resource
    Prediction of the binding site of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine in acetylcholinesterase by docking studies with the SYSDOC program (1994)
    Springer
    Journal of computer aided molecular design 8 (1994), S. 683-693 
    Details
    ISSN: 1573-4951
    Keywords: Molecular recognition ; E2020 ; Acetylcholinesterase inhibitors ; Alzheimer's disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary In the preceding paper we reported on a docking study with the SYSDOC program for predicting the binding sites of huperzine A in acetylcholinesterase (AChE) [Pang, Y.-P. and Kozikowski, A.P., J. Comput.-Aided Mol. Design, 8 (1994) 669]. Here we present a prediction of the binding sites of 1-benzyl-4-[(5,6-dimethoxy-1-indanon-2-yl)methyl]piperidine (E2020) in AChE by the same method. E2020 is one of the most potent and selective reversible inhibitors of AChE, and this molecule has puzzled researchers, partly due to its flexible structure, in understanding how it binds to AChE. Based on the results of docking 1320 different conformers of E2020 into 69 different conformers of AChE and on the pharmacological data reported for E2020 and its analogs, we predict that both the R- and the S-isomer of E2020 span the whole binding cavity of AChE, with the ammonium group interacting mainly with Trp84, Phe330 and Asp72, the phenyl group interacting mainly with Trp84 and Phe330, and the indanone moiety interacting mainly with Tyr70 and Trp279. The topography of the calculated E2020 binding sites provides insights into understanding the high potency of E2020 in the inhibition of AChE and provides hints as to possible structural modifications for identifying improved AChE inhibitors as potential therapeutics for the palliative treatment of Alzheimer's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00124015
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  • 7
    Electronic Resource
    Electronic Resource
    Rational design of novel neurotensin mimetics: Discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist (1994)
    Springer
    Journal of computer aided molecular design 8 (1994), S. 433-440 
    Details
    ISSN: 1573-4951
    Keywords: Drug design ; Multiple Template Approach ; Neurotensin agonist ; Neurotensin antagonist
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary We report the rational design of novel neurotensin mimetics through use of the Multiple Template Approach. This approach is based on our notion that a flexible peptide can be replaced by a partially flexible molecule, identified through testing a comparatively small number of molecules possessing a different intrinsic availability of conformations of the native peptide. The Multiple Template Approach has culminated in the discovery of a pharmacologically unprecedented agent, which behaves as a neurotensin antagonist at low concentration and as a full neurotensin agonist at high concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00125377
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  • 8
    Electronic Resource
    Electronic Resource
    Applications of free energy derivatives to analog design (1995)
    Springer
    Perspectives in drug discovery and design 3 (1995), S. 106-122 
    Details
    ISSN: 1573-9023
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Summary Free energy derivatives, which were first used to analyze the sensitivity and the convergence of free energy calculations, have recently been proposed for use in analog design. In this article, we review the published applications of free energy derivatives to analog design, discuss the possible reasons for the success and failure of such applications, and describe our recent study on an alternative use of free energy derivatives in analog design. It is too early to definitively evaluate the usefulness of the free energy derivative method to yield valuable insights into analog design. Our recent study suggests that free energy derivatives hold promise in evaluating possible different binding sites for a given ligand and suggesting the sites of a ligand that are not suitable for further structural modifications.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02174469
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  • 9
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    Models of Ternary Complexes for Nonpeptidic Farnesyltransferase Inhibitors: Insights into Structure-Based Screen and Design of Potential Anticancer Therapeutics (1999)
    Springer
    Details
    Publication Date: 1999-10-29
    Print ISSN: 1610-2940
    Electronic ISSN: 0948-5023
    Topics: Chemistry and Pharmacology
    Published by Springer
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  • 10
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    Docking Studies on the Complexed and Uncomplexed FKBP12 Structures with Bound and Unbound Ligands: An Implication of a Conformational Selection Mechanism for Binding (1997)
    Springer
    Details
    Publication Date: 1997-07-31
    Print ISSN: 1610-2940
    Electronic ISSN: 0948-5023
    Topics: Chemistry and Pharmacology
    Published by Springer
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