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Jeffry D Madura

Publications and source records attributed to Jeffry D Madura.

14 recordsLinked to original sources
PubMed2006

Structure modeling, ligand binding, and binding affinity calculation (LR-MM-PBSA) of human heparanase for inhibition and drug design.

Human heparanase is an endo-beta-D-glycosidase that cleaves heparan sulphate (HS) chains in the extracellular matrix and basement membrane. It is known that the cleavage of HS by heparanase results in cell invasion and metastasis of cancer. Therefore, heparanase is considered an important target for cancer drug development. The three-dimensional structure of heparanase would be useful in the rational design of inhibitors targeted to the enzyme; however, the three-dimensional structure has not yet been determined. In our effort to design inhibitors, we developed a three-dimensional structure of heparanase using a homology-modeling approach. The homology-built structure is consistent to previous bioinformatics and site-mutation experimental results. The heparanase features a (alpha/beta)(8) TIM-barrel fold with two glutamate residues (Glu225 and Glu343) located in the active-site cleft. This feature supports the putative mechanism of proton donor and nucleophilic sites. Docking simulations yielded 41 complex structures, which indicate that the bound inhibitor could block ligand binding into the catalytic site. A free energy of binding model was established for 25 heparanase inhibitors with a training set of 25 heparanase inhibitors using the linear response MM-PBSA approach (LR-MM-PBSA). The correlation between calculated and experimental activity was 0.79 and the reliability of the model was validated with leave-one-out cross-validation method. Its predictive capability was further validated using a test set of 16 inhibitors similar to the training set of inhibitors. The correlation between the predicted and observed activities is significantly improved by the protein "induced-fit" that accounts for the flexibility of the receptor. These interaction and pharmacophore elements provide a unique insight to the rational design of new ligands targeted to the enzyme.

Amino Acid Sequence↗
PubMed2006

HIV-1 RT nonnucleoside inhibitors and their interaction with RT for antiviral drug development.

Non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) have become an inherent component of highly active antiretroviral therapy (HAART) in the treatment of human immunodeficiency virus type 1 (HIV-1) infections. One of the most serious problems associated with NNRTIs is that the virus exhibits resistance to the drug through mutation once the virus is exposed to the drug. New inhibitors effective against these mutants and resistant to new mutations are needed in the treatment of HIV-1 infection. Most mutations are such that larger side chain amino acids are replaced with a smaller side chain. Structural and computational approaches have been used to study the interaction between the NNRTI and RT and the dynamics of wild type mutated RT with and without a bound NNRTI to help understand the mechanism of inhibition and NNRTI resistance. It is still not understood how a NNRTI binding in a pocket, 10 A away the polymerase active site, affects the activity of RT, although several hypotheses have been suggested. Therefore, the focus for the development of next generation NNRTIs has to be the design of compounds with an improved resistance profile. Elucidating the mechanism of the interaction between NNRTI and RT is critical if structure-based drug development for HIV-1 RT is to be successful. This calls for a better understanding of the resistance mechanism by crystallographic and computational studies. This review will take a critical look at the numerous computational studies on HIV-RT and compare those results against the current structural and experimental data available.

Drug Design↗
PubMed2005

Effect of a bound non-nucleoside RT inhibitor on the dynamics of wild-type and mutant HIV-1 reverse transcriptase.

HIV-1 reverse transcriptase (RT) is an important target for drugs used in the treatment of AIDS. Drugs known as non-nucleoside RT inhibitors (NNRTI) appear to alter the structural and dynamical properties of RT which in turn inhibit RT's ability to transcribe. Molecular dynamics (MD), principal component analysis (PCA), and binding free energy simulations are employed to explore the dynamics of RT and its interaction with the bound NNRTI nevirapine, for both wild-type and mutant (V106A, Y181C, Y188C) RT. These three mutations commonly arise in the presence of nevirapine and result in resistance to the drug. We show that a bound NNRTI hinders the motion of almost all RT amino acids. The mutations, located in the non-nucleoside RT inhibitor binding pocket, partially restore RT flexibility. The binding affinities calculated by molecular mechanics/Poisson-Boltzmann surface accessibility (MM-PBSA) show that nevirapine interacts stronger with wild-type RT than with mutant RT. The mutations cause a loss of van der Waals interactions between the drug and the binding pocket. The results from this study suggest that a good inhibitor should efficiently enter and maximally occupy the binding pocket, thereby interacting effectively with the amino acids around the binding pocket.

Amino Acid Substitution↗
PubMed2005

Molecular dynamics simulation studies of the effect of phosphocitrate on crystal-induced membranolysis.

In this study, following our earlier work on calcium pyrophosphate dihydrate (CPPD) crystal-induced membranolysis, we demonstrate, using the CHARMM method of molecular dynamics simulation, the protective role of phosphocitrate (PC) against solvated dimyristoyl phosphatidylcholine phospholipid bilayer disintegration on contact with the CPPD crystal. Our molecular dynamics simulations studies show that coverage of the CPPD crystal with a layer of phosphocitrate molecules results in the conservation of phospholipid bilayer integrity. We show that the rupture of the lipid bilayer in presence of CPPD and the protective effect of PC are primarily due to electrostatic interactions. The protective role of PC, which may also play an important and potentially therapeutic function against crystal-induced membranolysis is also discussed.

Animals↗
PubMed2004

Relative free energy of binding and binding mode calculations of HIV-1 RT inhibitors based on dock-MM-PB/GS.

Tetrahydroimidazo-[4,5,l-jk][1,4]-benzodiazepin-2-(1H)-one (TIBO) derivatives are important nonnucleoside human immunodeficiency virus-1 reverse transcriptase inhibitors (NNRTI). Several TIBO derivatives have shown high potency to inhibit reverse transcriptase (RT) and one (Tivirapine) has entered into clinical trials. The free energy of binding (FEB) is a numerical way to express the binding affinity of a ligand to its receptor and has been applied in screening candidates in rational drug design. In this work, the FEB of 42 TIBOs in RT was studied. Relative FEB is expressed in the form of a linear combination of vdW, electrostatic, solvation, and nonpolar solvation energy terms. The predicted FEB activity of the TIBOs studied has a good correlation (r(2) = 0.8680, q(2) = 0.8298) with respect to the experimental activity (pIC(50)). Based on the data reported here, the Finite Difference Poisson Boltzmann with a Gaussian Smooth Dielectric Constant Function method (PB/GS) solvation energy term is very important in predicting the binding affinity of TIBOs in RT. In summary, the Dock-Molecular Mechanics (MM)-PB/GS method is a promising technique in predicting ligand/receptor binding affinity and it can be used to screen relatively large sets of molecules in a reasonable amount of computer time.

Anti-HIV Agents↗
PubMed2004

Development of an improved four-site water model for biomolecular simulations: TIP4P-Ew.

A re-parameterization of the standard TIP4P water model for use with Ewald techniques is introduced, providing an overall global improvement in water properties relative to several popular nonpolarizable and polarizable water potentials. Using high precision simulations, and careful application of standard analytical corrections, we show that the new TIP4P-Ew potential has a density maximum at approximately 1 degrees C, and reproduces experimental bulk-densities and the enthalpy of vaporization, DeltaH(vap), from -37.5 to 127 degrees C at 1 atm with an absolute average error of less than 1%. Structural properties are in very good agreement with x-ray scattering intensities at temperatures between 0 and 77 degrees C and dynamical properties such as self-diffusion coefficient are in excellent agreement with experiment. The parameterization approach used can be easily generalized to rehabilitate any water force field using available experimental data over a range of thermodynamic points.

Computer Simulation↗
PubMed2004

Methods for applying the quantitative structure-activity relationship paradigm.

There are several Quantitative Structure-Activity Relationship (QSAR) methods to assist in the design of compounds for medicinal use. Owing to the different QSAR methodologies, deciding which QSAR method to use depends on the composition of system of interest and the desired results. The relationship between a compound's binding affinity/activity to its structural properties was first noted in the 1930s by Hammett and later refined by Hansch and Fujita in the mid-1960s. In 1988 Cramer and coworkers created Comparative Molecular Field Analysis (CoMFA) incorporating the three-dimensional (3D) aspects of the compounds, specifically the electrostatic fields of the compound, into the QSAR model. Hopfinger and coworkers included an additional dimension to 3D-QSAR methodology in 1997 that eliminated the question of "Which conformation to use in a QSAR study?", creating 4D-QSAR. In 1999 Chemical Computing Group Inc. (CCG) developed the Binary-QSAR methodology and added novel 3D-QSAR descriptors to the traditional QSAR model allowing the 3D properties of compounds to be incorporated into the traditional QSAR model. Recently CCG released Probabilistic Receptor Potentials to calculate the substrate's atomic preferences in the active site. These potentials are constructed by fitting analytical functions to experimental properties of the substrates using knowledge-based methods. An overview of these and other QSAR methods will be discussed along with an in-depth examination of the methodologies used to construct QSAR models. Also, included in this chapter is a case study of molecules used to create QSAR models utilizing different methodologies and QSAR programs.

Algorithms↗
PubMed2003

Family 18 chitinase-oligosaccharide substrate interaction: subsite preference and anomer selectivity of Serratia marcescens chitinase A.

The sizes and anomers of the products formed during the hydrolysis of chitin oligosaccharides by the Family 18 chitinase A (ChiA) from Serratia marcescens were analysed by hydrophilic interaction chromatography using a novel approach in which reactions were performed at 0 degrees C to stabilize the anomer conformations of the initial products. Crystallographic studies of the enzyme, having the structure of the complex of the ChiA E315L (Glu315-->Leu) mutant with a hexasaccharide, show that the oligosaccharide occupies subsites -4 to +2 in the substrate-binding cleft, consistent with the processing of beta-chitin by the release of disaccharide at the reducing end. Products of the hydrolysis of hexa- and penta-saccharides by wild-type ChiA, as well as by two mutants of the residues Trp275 and Phe396 important in binding the substrate at the +1 and +2 sites, show that the substrates only occupy sites -2 to +2 and that additional N -acetyl-D-glucosamines extend beyond the substrate-binding cleft at the reducing end. The subsites -3 and -4 are not used in this four-site binding mode. The explanation for these results is found in the high importance of individual binding sites for the processing of short oligosaccharides compared with the cumulative recognition and processive hydrolysis mechanism used to digest natural beta-chitin.

Binding Sites↗
PubMed2003

Kinetic and docking studies of the interaction of quinones with the quinone reductase active site.

NAD(P)H/quinone acceptor oxidoreductase type 1 (QR1) protects cells from cytotoxic and neoplastic effects of quinones though two-electron reduction. Kinetic experiments, docking, and binding affinity calculations were performed on a series of structurally varied quinone substrates. A good correlation between calculated and measured binding affinities from kinetic determinations was obtained. The experimental and theoretical studies independently support a model in which quinones (with one to three fused aromatic rings) bind in the QR1 active site utilizing a pi-stacking interaction with the isoalloxazine ring of the FAD cofactor.

Animals↗
PubMed2002

Docking of non-nucleoside inhibitors: neotripterifordin and its derivatives to HIV-1 reverse transcriptase.

The docking of small molecules to proteins has played an important role in the understanding of drug/receptor interactions. An important drug/receptor interaction is between non-nucleoside inhibitors of HIV-1 RT and the non-nucleoside binding pocket. We report the results of docking calculations in which we have docked known and proposed non-nucleoside reverse transcriptase inhibitors to the type 1 virus. The proposed NNRTIs dock in a similar position and orientation as known inhibitors. In addition, we observe a linear correlation between the calculated interaction energy and EC50 for the inhibitors, suggesting that the docked structure orientation and the interaction energies are reasonable. Two hydrogen bonds between nevirapine and RT (3HVT and 1VRT) are observed and are reproduced across different docking schemes. Since we used two different HIV-1 RT crystal structures (3HVT and 1VRT), which are at different levels of resolution (2.9 and 2.2 A, respectively), we propose that structures with resolutions better than 3 A can be used to produce reasonable docking results.

Anti-HIV Agents↗
PubMed2002

Effective computational modeling of constitutional isomerism and aggregation states of explicit solvates of lithiated phenylacetonitrile.

We present the first calculations which accurately account for the position of metalation and aggregation state of lithiated nitriles. Solvation is found to be a key determinant of structure. Five known solvates of lithiated phenylacetonitrile were examined computationally to determine the minimum level of theory required to reproduce the observed X-ray and multinuclear NMR structures. In all cases Hartree-Fock 3-21G energies of explicit solvates calculated at PM3 geometries correctly predict the observed N-lithiated constitutional isomer. Selected density functional theory (B3LYP/6-31+G*//PM3) energy calculations reproduce this trend. We also show that 3-21G//PM3 calculations which do not include explicit solvent molecules, or which include water as a model for diethyl ether, may lead to incorrect predictions of the preferred constitutional isomer. 3-21G//PM3 energies also adequately account for observed aggregation states of the TMEDA, diethyl ether, and THF solvates. Finally, calculations of THF-solvated monomers up to the B3LYP/6-31+G*//B3LYP/6-31+G level indicate a significant (6.8 kcal/mol) preference for N-lithiation.

Journal Article↗
PubMedDate not supplied

An introduction to simulation and visualization of biological systems at multiple scales: a summer training program for interdisciplinary research.

Advances in biomedical research require a new generation of researchers having a strong background in both the life and physical sciences and a knowledge of computational, mathematical, and engineering tools for tackling biological problems. The NIH-NSF Bioengineering and Bioinformatics Summer Institute at the University of Pittsburgh (BBSI @ Pitt; www.ccbb.pitt.edu/bbsi) is a multi-institutional 10-week summer program hosted by the University of Pittsburgh, Duquesne University, the Pittsburgh Supercomputing Center, and Carnegie Mellon University, and is one of nine Institutes throughout the nation currently participating in the NIH-NSF program. Each BBSI focuses on a different area; the BBSI @ Pitt, entitled "Simulation and Computer Visualization of Biological Systems at Multiple Scales", focuses on computational and mathematical approaches to understanding the complex machinery of molecular-to-cellular systems at three levels, namely, molecular, subcellular (microphysiological), and cellular. We present here an overview of the BBSI @ Pitt, the objectives and focus of the program, and a description of the didactic training activities that distinguish it from other traditional summer research programs. Furthermore, we also report several challenges that have been identified in implementing such an interdisciplinary program that brings together students from diverse academic programs for a limited period of time. These challenges notwithstanding, presenting an integrative view of molecular-to-system analytical models has introduced these students to the field of computational biology and has allowed them to make an informed decision regarding their future career prospects.

Computational Biology↗
PubMedDate not supplied

CoMFA 3D-QSAR analysis of HIV-1 RT nonnucleoside inhibitors, TIBO derivatives based on docking conformation and alignment.

HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as nonnucleoside RT inhibitors (NNRTIs) and nucleoside analogues. NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTI category, there is a set of inhibitors commonly referred to as TIBO inhibitors. Fifty TIBO inhibitors were used in the work to build 3-D QSAR models. The two known crystal structures of complexes are used to investigate and validate the docking protocol. The results show that the docking simulations reproduce the crystal complexes very well with RMSDs of approximately 1 A and approximately 0.6 A for 1REV and 1COU, respectively. The alignment of molecules and "active" conformation selection are the key to a successful 3D-QSAR model by CoMFA. The flexible docking (Autodock3) was used on determination of "active" conformation and molecular alignment, and CoMFA and CoMSIA were used to develop 3D-QSAR models of 50 TIBOs in the work. The 3D-QSAR models demonstrate a good ability to predict the activity of studied compounds (r2 = 0.972, 0.944, q2 = 0.704, 0.776). It is shown that the steric and electrostatic properties predicted by CoMFA contours can be related to the binding structure of the complex. The results demonstrate that the combination of ligand-based and receptor-based modeling is a powerful approach to build 3D-QSAR models.

Benzodiazepines↗