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Biomedical subjects

B L Podlogar

Publications and source records attributed to B L Podlogar.

9 recordsLinked to original sources
PubMed2001

"Holistic" in silico methods to estimate the systemic and CNS bioavailabilities of potential chemotherapeutic agents.

A fundamental fact in the drug development process is that physical quantity of chemical substance is needed for experimental determinations. Information that could guide the course of a drug discovery program, in particular the penultimate ADME parameters % oral bioavailability (%F) and CNS permeability (BBB) are not explicitly determined until after large capital, human and time resources have been invested in a particular chemical series to produce the substance. To assure better go/no-go decisions and to protect the risks of a process that necessitates a considerable "front-loading" of resources, project teams are turning to computational methods to estimate these parameters. Herein we provide a detailed review of "holistic" in silico methods toward the estimation of %F and BBB. An unbiased description of the scope and limitations of their installation and application will be given in the context of an on going pharmaceutical project.

Administration, Oral↗
PubMed2001

Computational methods to estimate drug development parameters.

Computational methods are currently available to estimate oral bioavailability, solubility, metabolism, toxicity, pKa, blood-brain barrier permeability and other ADME and physicochemical parameters. Decisions as to which methods to implement and to employ must be made in accordance with the stated goals of a drug discovery organization, the timeline for these goals, and the budgetary limitations as set forth to accomplish these goals. Certain methods are more attractive to the production environment of a pharmaceutical project team where early ADME and Tox information is sought to aid in drug design decisions and prioritization. Practical limitations of these methods, ease of use, utility of results, as well as their scope and limitations are discussed. Recommendations as to which parameters are best estimated by commercial products, as opposed to those that can be developed in-house, are delineated. Special attention is given to those methods that can be integrated into the current high-throughput paradigms of drug discovery programs. Together, these considerations define a 'zero-infrastructure' approach to provide ADME and Tox information during the early stages of the drug design process.

Animals↗
PubMed2000

Synthesis and evaluation of 4-(N,N-diarylamino)piperidines with high selectivity to the delta-opioid receptor: a combined 3D-QSAR and ligand docking study.

A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.

Amino Acid Sequence↗
PubMed1998

Conformational analysis of the endogenous mu-opioid agonist endomorphin-1 using NMR spectroscopy and molecular modeling.

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) is a highly selective and potent agonist of the mu-opioid receptor. To identify structural attributes unique to this opioid peptide and potential sites of recognition, a conformational analysis has been performed using multidimensional NMR and molecular modeling techniques. The spectroscopic results, derived from experiments in both DMSO and water, indicate that endomorphin-1 exists in the cis- and trans-configuration with respect to the Pro-omega bond in approximately 25% and 75% populations, respectively. In DMSO, the cis-configuration adopts a compact sandwich conformation in which the Tyr and Trp aromatic rings pack against the proline ring, whereas the trans-configuration adopts an extended conformation. Although non-random structure was not observed in water, condensed phase molecular dynamics calculations indicate that trans-isomers dominate the population in this higher dielectric medium. Structural comparison of the cis- and trans-configurations with morphine and selective mu-peptide ligands PL-017 and D-TIPP, as well as the delta-selective peptide ligands TIPP (delta-antagonist, mu-agonist) and DPDPE were also performed and suggest the trans-isomer is likely the bioactive form. A hypothesis is proposed to explain mu- and delta-selectivity based on the presence of spatially distinct selectivity pockets among these ligands.

Computer Simulation↗
PubMed1997

Protein structure determination using a combination of comparative modeling and NMR spectroscopy. Application to the response regulator protein, Spo0F.

A practical combination of comparative modeling and NMR spectroscopy was used to generate a three-dimensional structure of the response regulator protein, Spo0F. The backbone structure obtained compares to the Spo0F Y13S mutant X-ray structure with an rmsd of 2.0 A. We provide results which suggest that structures obtained by this method are suitable for drug discovery. The results of the GRID and DOCK methods as applied to the model and X-ray structures of Spo0F are remarkably similar and tend to suggest the same design conclusions. This trend is illustrated by these same techniques applied to two experimentally derived structures of the analogous protein, CheY, which exhibit a pairwise rmsdBB on the same order as that found for the two Spo0F structures.

Amino Acid Sequence↗
PubMed1997

DNA gyrase inhibitory and antimicrobial activities of some diphenic acid monohydroxamides.

The synthesis and inhibitory activity against DNA gyrase of a series of diphenic acid monohydroxamides 4a-f are described. A protocol of two biological assays showed conclusively that inhibition occurs specifically at the DNA-DNA gyrase complex and is not attributable to nonspecific inhibition. In the enzyme assays, 4c was potent as the prototypical quinolone, nalidixic acid (1), with an IC50 value of 58.3 micrograms/mL compared to 52 micrograms/mL for 1. MIC activity against bacterial strains showed a systematic drop for all compounds relative to 1. For compounds 4c-e, the addition of PMBN produced dramatic increases in MIC activity indicating that activity is likely to be related to membrane transport. Molecular modeling of 4a indicates that the diphenic acid monohydroxamides can bind to the DNA-DNA gyrase complex in a similar fashion as that hypothesized for the quinolone series according to the hypothesis suggested by Shen et al. but may not self-associate by pi-pi stacking. In contrast to the quinolone series, as the diphenic acid monohydroxamides are shown by molecular mechanics minimizations to be nonplanar, they may present novel approaches for chemotherapeutic intervention with a potential for decreased side effects.

Anti-Bacterial Agents↗
PubMed1994

Design, synthesis, and conformational analysis of a novel macrocyclic HIV-protease inhibitor.

Design modifications to the lead HIV-PR inhibitor 1 (MDL 73,669, Ki = 5 nM) have been postulated based on a computational model of the 1/HIV-PR complex. A novel macrocyclic inhibitor 8 (MDL 104,168) wherein the P1 and P3 side chains of the original acyclic inhibitor have been joined retains good biological activity (Ki = 20 nM). NMR analysis of the precursor alcohol (S)-7 shows the conformation of the cyclic region to be very similar to that observed in the enzyme-bound 8 as determined by the computational model. Consistency of the computational model with NMR data and in vacuo molecular dynamics simulations provide the basis for postulating further modifications of the cyclic inhibitor expected to optimize its interactions with HIV-PR.

Amino Acid Sequence↗