Elaine R. Maia

The search for new DHFR inhibitors: a review of patents, January 2001 – February 2005

During the past 5 years, intense research activity has come from both private companies and academic institutions, aimed at the discovery of new, effective dihydrofolate reductase (DHFR) inhibitors. This important enzyme was discovered in the late 1950s, and, after nearly five decades, it still continues to draw the attention of researchers worldwide. Its low molecular weight makes it ideal as one of the main tools in molecular biology research: that is, in X-ray crystallography, NMR spectroscopy, kinetic measurements, and site-directed mutagenesis. This review will focus on the most recent developments published in the field, paying particular attention to promising DHFR inhibitors, their chemistry and biological evaluation, and to new chemical and pharmaceutical processes.

Interactions of 5-deazapteridine Derivatives with Mycobacterium tuberculosis and with Human Dihydrofolate Reductases

Abstract There are major differences between the structures of human dihydrofolate reductase (hDHFR) and Mycobacterium tuberculosis dihydrofolate reductase (mtDHFR). These differences may allow us to design more selective mtDHFR inhibitors. In this paper we study the reactions of six different compounds derived from 5-deazapteridine with human and bacterial enzymes. Results suggest that the addition of hydrophobic groups to the aminophenyl ring would increase mtDHFR-inhibitor affinity and selectivity.

The hypermodified Y base electrostatic contribution to the energetics of the codon-anticodon pairing in tRNAPhe

We report ab initio results at the Hartree-Fock/6–31G level for the energetics of the codon-anticodon pairing in tRNAPhe. We have employed a molecular dynamics protocol in order to relax the studied crystallographic structure. Electrostatic potentials due to the presence of the hypermodified Y base and a guanine base in position 37 of the anticodon loop are compared. The results of the electrostatic potentials on the planes containing the molecules of the complementary codon bases UUC, indicate a strong energetic stabilization when a Y base is present, in comparison to the substitution by a guanine base. The present results provide some molecular data on the energetics of the codon-anticodon pairing mechanism and are related to experimental studies which suggest that hypermodification in tRNAs contribute to the regulation of gene expression.

Docking simulations and QM/MM studies between isoniazid prodrug, catalase-peroxidase (KatG) and S315T mutant from Mycobacterium tuberculosis

Isoniazid (INH), an antibiotic used to treat tuberculosis (TB), is a prodrug requiring activation by the Mycobacterium tuberculosis KatG (mtKatG). In the present work, theoretical calculations were carried out to locate the most energetically-favorable INH–KatG interaction modes using the experimental structure of a wild type and mutant mtKatG active site. The S315T mutation significantly affects the ability of the enzyme to convert INH to isonicotinic acid in vitro. The results showed that significant changes occur in the INH binding pattern when serine is replaced by threonine.

Computational approach for the design of AP1867 analogs: aiming at new synthetic routes for potential immunosuppressant agents.

Abstract Molecular modelling and synthetic arguments are valuable tools for the design of potential immunosuppressant agents. In this paper, eight proline-based compounds related to the AP1867 structure are studied and at least one of them is found to be a structurally good candidate for the inhibition of FKBP protein. Theoretical calculations were carried out to locate the most energetically favorable chemical substituent group relative to a core skeleton group on interaction with the FKBP binding cavity. Connolly accessible surface calculations have complemented the molecular mechanics and dynamics approaches. Calculated results were also analyzed on the basis of hydrogen bond interactions, relative energies of interaction, root-mean square deviations of amino acid residues of the crystallized protein, and orientation of the substituent groups within the active site. The results show a significant reduction in the relative interaction energies and very good shape complementarities between our final analog compound and the FKBP binding pocket.

Molecular dynamics studies of amylose plasticized with Brazilian Cerrado oils: part I

1Laboratório de Estudos Estruturais Moleculares – LEEM, Instituto de Química – IQ, Universidade de Brasília – UnB, Campus Darcy Ribeiro, Brasília, DF, Brasil 2Laboratório de Pesquisa em Polímeros e Nanomateriais – LabPolN, Instituto de Química – IQ, Universidade de Brasília – UnB, Campus Darcy Ribeiro, Brasília, DF, Brasil 3Laboratoire d’Ingénierie des Biomolécules – LIBio, Ecole Nationale Supérieure d’Agronomie et des Industries Alimentaires – ENSAIA, Institut National Polytechnique de Lorraine – INPL, Université de Lorraine – UL, Vandœuvre-lès-Nancy, France