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At least 91 records · Page 5Linked to original sources
PubMed1999

Molecular modeling of the intrastrand guanine-guanine DNA adducts produced by cisplatin and oxaliplatin.

Intrastrand DNA adducts formed by cisplatin and oxaliplatin were modeled with molecular mechanics minimization and restrained molecular dynamics simulations in a comparative study. A reasonable set of force field parameters for the Pt atom were refined by using the available cisplatinated DNA crystal structure as a guide. This crystal structure was also used as the starting structure for the simulations. Analysis of the resulting structures indicated that the covalent effects of oxaliplatin coordination on DNA structure were very similar to those of cisplatin. The most prominent difference between the two structures resulted from the presence of the 1,2-diaminocyclohexane ring in the oxaliplatin adduct. The modeling indicated that this ring protrudes directly outward into, and fills much of, the narrowed major groove of the bound DNA, forming a markedly altered and less polar major groove in the area of the adduct. The differences in the structure of the adducts produced by cisplatin and oxaliplatin are consistent with the observation that they are differentially recognized by the DNA mismatch repair system.

Antineoplastic Agents↗
PubMed1994

Characterization of monoclonal anti-furosemide antibodies and molecular modeling studies of cross-reactive compounds.

Four mouse monoclonal antibodies directed against furosemide have been isolated and characterized. The cross-reactivity of the antibodies with eight compounds which are structurally and/or functionally related to furosemide was determined using a competition ELISA. All of the compounds, including furosemide, were then modeled using molecular mechanical and quantum mechanical methods in an attempt to correlate antibody binding with the conformational and electronic properties of the molecules. The results of these experiments demonstrated that all of the cross-reactivity observed could be readily explained using these techniques. Furthermore, these results should allow for more accurate prediction of unexpected cross-reactivities with these antibodies when they are used in immunoassays for determination of furosemide.

Animals↗
PubMed2004

Myosin regulatory domain orientation in skeletal muscle fibers: application of novel electron paramagnetic resonance spectral decomposition and molecular modeling methods.

Reorientation of the regulatory domain of the myosin head is a feature of all current models of force generation in muscle. We have determined the orientation of the myosin regulatory light chain (RLC) using a spin-label bound rigidly and stereospecifically to the single Cys-154 of a mutant skeletal isoform. Labeled RLC was reconstituted into skeletal muscle fibers using a modified method that results in near-stoichiometric levels of RLC and fully functional muscle. Complex electron paramagnetic resonance spectra obtained in rigor necessitated the development of a novel decomposition technique. The strength of this method is that no specific model for a complex orientational distribution was presumed. The global analysis of a series of spectra, from fibers tilted with respect to the magnetic field, revealed two populations: one well-ordered (+/-15 degrees ) with the spin-label z axis parallel to actin, and a second population with a large distribution (+/-60 degrees ). A lack of order in relaxed or nonoverlap fibers demonstrated that regulatory domain ordering was defined by interaction with actin rather than the thick filament surface. No order was observed in the regulatory domain during isometric contraction, consistent with the substantial reorientation that occurs during force generation. For the first time, spin-label orientation has been interpreted in terms of the orientation of a labeled domain. A Monte Carlo conformational search technique was used to determine the orientation of the spin-label with respect to the protein. This in turn allows determination of the absolute orientation of the regulatory domain with respect to the actin axis. The comparison with the electron microscopy reconstructions verified the accuracy of the method; the electron paramagnetic resonance determined that axial orientation was within 10 degrees of the electron microscopy model.

Actins↗
PubMed1996

Synthesis, structure-activity relationships, and molecular modeling studies of N-(indol-3-ylglyoxylyl)benzylamine derivatives acting at the benzodiazepine receptor.

A number of N-(indol-3-ylglyoxylyl)benzylamine derivatives were synthesized and tested for [3H]flunitrazepam displacing activity in bovine brain membranes. Some of these derivatives (9, 12, 14, 15, 17, 27, 34, 35, 38, 41, and 45) exhibited high affinity for the benzodiazepine receptor (BzR) with Ki values ranging from 67 to 11 nM. The GABA ratio and [35S]-tert-butylbicyclophosphorothionate binding data, determined for the most active compounds, showed that they elicit an efficacy profile at the BzR which depends on the kind of substituent present on the phenyl ring of the benzylamine moiety. Moreover, lengthening (propylamine derivatives 1-3) and shortening (aniline derivatives 46-54) of the distance between the phenyl ring and the amide group of the side chain gave compounds with a drastically lower binding potency. The biological results are discussed in the light of a recently proposed pharmacophore model and compared, by molecular modeling studies, with those obtained from effective BzR ligands.

Animals↗
PubMed2006

Conformational flexibility of mammalian cytochrome P450 2B4 in binding imidazole inhibitors with different ring chemistry and side chains. Solution thermodynamics and molecular modeling.

Recent x-ray structures of cytochrome P450 2B4 (CYP2B4) reveal an open form that undergoes a large-scale structural transition to a closed form upon binding to 4-(4-chlorophenyl)imidazole (4-CPI). Here, we report for the first time a complete solution thermodynamic study using isothermal titration calorimetry supported by spectroscopic studies to elucidate the conformational flexibility of CYP2B4 in binding imidazole inhibitors with different ring chemistry and side chains: 4-CPI, 1-benzylimidazole (1-BI), 1-CPI, 4-phenylimidazole (4-PI), 1-(2-(benzyloxy)ethyl)imidazole (BEI), and 1-PI. Each of the inhibitors induced type II spectral changes, and IC50 values for enzyme inhibition ranged from 0.1 to 2.4 microM, following the order 1-BI < 4-CPI < 1-CPI < 4-PI < BEI < 1-PI. Calorimetric titrations using monomeric enzyme yielded a 1:1 binding stoichiometry, with the associated KD values ranging from 0.3 to 4.8 microM and following the same rank order as the IC50 values. Changes in enthalpy at 25 degrees C ranged from -6.5 to -8.8 kcal mol(-1). The largest difference in binding entropy (+5.9 versus -4.1 cal mol(-1) K(-1)) was observed between 4-CPI and BEI, respectively, with a 2-fold difference in heat capacity changes (-604 versus -331 cal mol(-1) K(-1)), which is inferred to result from the reduction of apolar surface area of the enzyme ensuing from a conformational change upon 4-CPI binding. Accessibility to acrylamide of the only tryptophan (Trp121), which is located in helix C, was greatly decreased only in protein bound to 4-CPI. Steric restrictions hindered the perfect docking of only BEI to the closed conformation of the enzyme. The thermodynamic signature obtained for structurally similar inhibitors suggests remarkable plasticity of CYP2B4.

Acrylamides↗
PubMedDate not supplied

Molecular modeling of human cytochrome P450-substrate interactions.

The results of homology modeling of 10 human cytochrome P450 (CYP) enzymes involved in the Phase 1 metabolism of drugs and other foreign compounds are reported. The models have been constructed from the CYP102 hemoprotein domain template for which the substrate-bound crystallographic coordinates are available. Selective substrates of individual human P450s: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11 are all shown to fit within the corresponding enzymes' active sites in such a manner that is consistent with reported experimental data for both known pathways of substrate metabolism and from the results of site-directed mutagenesis, either in those particular human P450 enzymes concerned or for ones within the same subfamily. The self-consistency of these homology models indicates that they may have potential utility for the pre-screening of novel drug structures.

Cytochrome P-450 Enzyme System↗
PubMed2001

Derivation of Poisson and Nernst-Planck equations in a bath and channel from a molecular model.

Permeation of ions from one electrolytic solution to another, through a protein channel, is a biological process of considerable importance. Permeation occurs on a time scale of micro- to milliseconds, far longer than the femtosecond time scales of atomic motion. Direct simulations of atomic dynamics are not yet possible for such long-time scales; thus, averaging is unavoidable. The question is what and how to average. In this paper, we average a Langevin model of ionic motion in a bulk solution and protein channel. The main result is a coupled system of averaged Poisson and Nernst-Planck equations (CPNP) involving conditional and unconditional charge densities and conditional potentials. The resulting NP equations contain the averaged force on a single ion, which is the sum of two components. The first component is the gradient of a conditional electric potential that is the solution of Poisson's equation with conditional and permanent charge densities and boundary conditions of the applied voltage. The second component is the self-induced force on an ion due to surface charges induced only by that ion at dielectric interfaces. The ion induces surface polarization charge that exerts a significant force on the ion itself, not present in earlier PNP equations. The proposed CPNP system is not complete, however, because the electric potential satisfies Poisson's equation with conditional charge densities, conditioned on the location of an ion, while the NP equations contain unconditional densities. The conditional densities are closely related to the well-studied pair-correlation functions of equilibrium statistical mechanics. We examine a specific closure relation, which on the one hand replaces the conditional charge densities by the unconditional ones in the Poisson equation, and on the other hand replaces the self-induced force in the NP equation by an effective self-induced force. This effective self-induced force is nearly zero in the baths but is approximately equal to the self-induced force in and near the channel. The charge densities in the NP equations are interpreted as time averages over long times of the motion of a quasiparticle that diffuses with the same diffusion coefficient as that of a real ion, but is driven by the averaged force. In this way, continuum equations with averaged charge densities and mean-fields can be used to describe permeation through a protein channel.

Electrophysiology↗