Carlos Mauricio R. Sant'Anna

Modelagem Molecular: Uma Ferramenta para o Planejamento Racional de Fármacos em Química Medicinal

The molecular basis of modern therapeutics consist in the modulation of cell function by the interaction of microbioactive molecules as drug cells macromolecules structures. Molecular modeling is a computational technique developed to access the chemical structure. This methodology, by means of the molecular similarity and complementary paradigm, is the basis for the computer-assisted drug design universally employed in pharmaceutical research laboratories to obtain more efficient, more selective, and safer drugs. In this work, we discuss some methods for molecular modeling and some approaches to evaluate new bioactive structures in development by our research group.

Glossário de Termos Usados no Planejamento de Fármacos (Recomendações da IUPAC para 1997)

N.T.: Por se tratar de um campo de evolucao muito rapida, muitos termos novos surgiram desde a publicacao do glossario em lingua inglesa e a atual traducao. Este trabalho deve ser considerado como um esforco inicial para suprir as necessidades de padronizacao dos termos do planejamento computacional de farmacos na lingua portuguesa, os quais ja sao usados com frequencia em artigos de quimica medicinal publicados em nosso pais. N.T.: AMBER tambem refere-se ao campo de forca. Apesar deste campo de forca ter sido parametrizado e definido para proteinas e acidos nucleicos, parâmetros tem sido adicionados para estende-lo para calculos de outras classes de moleculas. N.T.: Na maior parte dos casos as relacoes quantitativas envolvem atividades farmacologicas, mas o metodo pode ser aplicado igualmente a conjuntos de moleculas planejadas para causar qualquer acao sobre organismos vivos, inclusive toxica, como e o caso dos pesticidas. N.T.: O metodo CoMFA tambem pode ser usado para a analise de relacoes quantitativas entre afinidades (por receptores, etc.) com propriedades fisicoquimicas tridimensionais. GLOSSARIO DE TERMOS USADOS NO PLANEJAMENTO DE FARMACOS (RECOMENDACOES DA IUPAC PARA 1997)

A semiempirical study of pyrazole acylhydrazones as potential antimalarial agents

In this work, we evaluated structural and electronic similarities between a new class of acylhydrazones, recently presented as effective inhibitors of a Plasmodium falciparum cysteine protease, and a series of pyrazole arylacylhydrazones with analgesic and antiaggregating (antithrombotic) properties, using AM1. The calculated results suggest that at least one of the pyrazole compounds is similar enough to the active compounds to be considered as a candidate for a future antimalarial series.

Toward a platelet-activating factor pseudoreceptor: Semiempirical modeling of cation-π and hydrogen bond interactions in agonist binding☆

Abstract The triggering of a platelet-activating factor (PAF) receptor by its natural agonist can ultimately result in many inflammatory and allergic pathologic states. Many PAF receptor antagonists have been developed during recent years as potential therapeutic agents for the treatment of these pathologies. The structural elucidation of the PAF receptor active site has not yet been implemented, but it can be anticipated as an important tool for the development of more efficient PAF antagonists. Pseudoreceptor modeling is a technique for the construction of a receptor surrogate for structurally uncharacterized bioregulators. We present here our initial results in the development of a PAF pseudoreceptor by means of simple probes as representatives of the active site amino acid residues bound to PAF agonist models. This simple model is composed of an aromatic probe and of a number of hydrogen bond donating probes. The semiempirical enthalpy of complexation of these probes, together with estimates of the entropic term of binding, prompted us to calculate relative theoretical free energies of binding, which correlate quite well with pharmacological results of PAF agonists from the literature.

Molecular modeling on platelet-activating factor (PAF) and new proposed PAF antagonists†

Platelet-activating factor (PAF) is an autacoid derived from cellular membrane phospholipids in response to chemical or physical stimuli. It has been identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphocholine; the alkyl group is composed of 16 or 18 carbon atoms in human cells. PAF can cause a series of pathophysiological effects, related to inflammatory and allergic diseases such as asthma, gastric ulcerations, transplant rejections, psoriasis, cerebral, renal, and myocardial ischemia. As PAF biological action is a result of interactions with specific receptors on target cells, several specific PAF receptor antagonists have been proposed for therapeutic control of the pathological states in which PAF is implicated. In this work we have calculated at AM1 level 16 conformations of a model (alkyl = octyl) of (R)-PAF. We have used these conformations and calculated structures of two hetrazepines (WEB 2086 and E 6123), FR 128998 and RP 59227, known antagonists of PAF activity currently under development, to test a recently proposed pharmacophore map. Our results suggest that the model is too rigid. Having this in mind, we used the pharmacophore model to evaluate the potential activity of a new series of proposed PAF receptor antagonists based on bicyclo[3.3.0]-2-oxaoctane. The results were used to decide which compounds should receive priority in synthesis. The synthetic results and pharmacological profiles of the new derivatives will be published elsewhere.

Semiempirical calculations on the mechanism of stereoselective NaBH4 reduction of 2-methoxycarbonyl-2-allyl-cyclopentanone

Abstract The stereoselective mechanism of reduction of 2-methoxycarbonyl-2-allyl-cyclopentanone with BH 4 − was investigated with the AM1 method in the gas phase. Geometries of reactants, transition states, and products were obtained for the reactions conducting to both trans and cis alkoxides. The results suggest that the stereoselectivity is of steric origin. The effect of a chelating Zn 2+ ion on the reaction stereoselectivity was analyzed.

Influence of the termonomer on the synthesis and properties of ethylene-propylene polymers

EPDM elastomers have been synthesized by the Ziegler-Natta oatalytic system VOCl3/Al2Et3Cl3 with the objetive of verifying the influence of termonomers on terpolymer synthesis and on the properties of peroxide-vulcanized terpolymer compositions. Two groups of termonomers have been studied. Dienes, i.e., dicyclopentadiene (DCP), 5-ethylidene-2-norbornene (ENB) and limonene, and aromatic compounds, i.e., indene (IND) and styrene (ST). The influence on the synthesis has been verified by yield, termonomer incorporation, and molecular weight distri bution. The vulcanizate properties have included mechanical and electrical properties.

An Unusual Intramolecular Halogen Bond Guides Conformational Selection.

PIK-75 is a phosphoinositide-3-kinase (PI3K) α-isoform-selective inhibitor with high potency. Although published structure-activity relationship data show the importance of the NO2 and the Br substituents in PIK-75, none of the published studies could correctly determine the underlying reason for their importance. In this publication, we report the first X-ray crystal structure of PIK-75 in complex with the kinase GSK-3β. The structure shows an unusual U-shaped conformation of PIK-75 within the active site of GSK-3β that is likely stabilized by an atypical intramolecular Br⋅⋅⋅NO2 halogen bond. NMR and MD simulations show that this conformation presumably also exists in solution and leads to a binding-competent preorganization of the PIK-75 molecule, thus explaining its high potency. We therefore suggest that the site-specific incorporation of halogen bonds could be generally used to design conformationally restricted bioactive substances with increased potencies.