Search results for "Drug Design"
showing 10 items of 232 documents
On the contribution of molecular topology to drug design and discovery.
2010
Abstract The role of molecular topology (MT) in the design and selection of new drugs is discussed. After an overview of the different in silico molecular design current technologies, the QSAR analysis is dealt in detail with particular emphasis in the use of topological indices as molecular descriptors. The results of the application of MT in drug design and discovery are described and finally a possible explanation is given about some of the key reasons explaining it's the extraordinary performance.
Advances in the molecular modeling and quantitative structure–activity relationship-based design for antihistamines
2013
Nowadays the use of antihistamines (AH) is increasing steadily. These drugs are able to act on a variety of pathological conditions of the organism. A number of computer-aided (in silico) approaches have been developed to discover and develop novel AH drugs. Among these methods stand the ones based on drug-receptor docking, thermodynamics, as well as the quantitative structure-activity relationships (QSAR).This review collates the most recent advances in the use of computer approaches for the search and characterization of novel AH drugs. Within the QSAR methods, particular attention will be paid to those based on molecular topology (MT) because of their demonstrated efficacy in discovering…
Design and Synthesis of 4-Substituted Indolo[3,2-e][1,2,3]triazolo[1,5-a]pyrimidine Derivatives with Antitumor Activity
2008
New derivatives of the indolo[3,2- e][1,2,3]triazolo[1,5- a]pyrimidine system, substituted in the 4 position, were designed as novel antitumor agents because of their theoretical capability to form stable complexes with DNA fragments. The calculated free energies of binding were found in the range -12.76 --> -39.68 Kcal/mol. The docking studies revealed a common binding mode with the chromophore intercalated between GC base pairs, whereas the side chain lies along the minor groove. Compounds, selected on the basis of the docking studies and suitably synthesized, showed antiproliferative activity against each type of tumor cell line investigated, generally in the low micromolar range. The mo…
Polyamine conjugates of stigmasterol.
2012
Abstract Three new polyamine conjugates with stigmasterol [(3β,22 E )-stigmasta-5,22-dien-3-ol] were synthesized and subjected to basic antimicrobial and cytotoxic tests. The conjugate derived from spermine, (3β,22 E )-stigmasta-5,22-dien-3-yl 4(12-amino-4,9-diaza-dodecylamino)-4-oxobutanoate ( 5c ), displayed considerable antimicrobial activity on Staphylococcus aureus at low concentration (50 μg mL −1 ). The cytotoxic activity was tested on cells of human T-lymfoblastic leukemia (IC 50 = 35.8 ± 10.3 μM ( 5c ) and IC 50 = 35.9 ± 5.7 μM ( 5b )) and normal human fibroblasts (IC 50 = 38.0 ± 2.8 μM ( 5c ) and IC 50 = 45.5 ± 1.9 μM ( 5b )). Conjugate 5a displayed no activity in both tests.
Application of molecular topology to the prediction of the antimalarial activity of a group of uracil-based acyclic and deoxyuridine compounds.
2008
A topological-mathematical model has been arranged to search for new derivatives of deoxyuridine and related compounds acting as antimalarials against Plasmodium falciparum. By using linear discriminant and multilinear regression analysis a model with two functions was capable to predict adequately the IC(50) for each compound of the training and test series. After carrying out a virtual screening based upon such a model, new structures potentially active against P. falciparum are proposed.
N-(INDAZOLYL)BENZAMIDO DERIVATIVES AS CDK1 INHIBITORS: DESIGN, SYNTHESIS, BIOLOGICAL ACTIVITY, AND MOLECULAR DOCKING STUDIES
2009
A series of N-1H-indazole-1-carboxamides has been synthesized and their effects on both CDK1/cyclin B and the K-562 (human chronic myelogenus leukemia) cell line were evaluated. Using a computational model, we have observed that all the most active compounds 9e, f, i-n exhibited the same binding mode of purvanalol A in the ATP-binding cleft. Although they were able to moderately inhibit the leukemic cell line K-562 and to show inhibitory activity against the Cdc2-Cyclin B kinase in the low micromolar range, they turned out to be non-cytotoxic against HuDe (IZSL) primary cell cultures from human derm. These preliminary results are quite encouraging in view of the low toxicity demonstrated by…
General topological patterns of known drugs.
2001
Abstract Discriminating “drug-like” from “non-drug-like” compounds is a relatively emerging topic within the drug research. The basic assumption is that it is possible to obtain relevant information from structural features common to the known drugs, in order to discard a huge number of candidate chemical structures with low probability of becoming drugs. A graph-theoretical contribution to this subject is reported in this paper, by making exclusive use of linear relationships. The results suggest that it is possible to achieve a pattern of general pharmacological activity based on molecular topology. Conclusions are tentative pending verification of the results with larger compound librari…
A molecular assembly system that renders antigens of choice highly repetitive for induction of protective B cell responses.
2002
Virus like particles (VLPs) are known to induce potent B cell responses in the absence of adjuvants. Moreover, epitope-specific antibody responses may be induced by VLPs that contain peptides inserted in their immunodominant regions. However, due to steric problems, the size of the peptides capable of being incorporated into VLPs while still permitting capsid assembly, is rather limited. While peptides genetically fused to either the N- or C-terminus of VLPs present fewer assembly problems, the immune responses obtained against such epitopes are often limited, most likely because the epitopes are not optimally exposed. In addition, such particles may be less stable in vivo. Here, we show th…
A Computational Study of the Protein-Ligand Interactions in CDK2 Inhibitors: Using Quantum Mechanics/Molecular Mechanics Interaction Energy as a Pred…
2006
ABSTRACT: We report a combined quantum mechanics/molecular mechanics (QM/MM) study to determine the protein-ligand interaction energy between CDK2 (cyclin-dependent kinase 2) and five inhibitors with the N2 -substituted 6-cyclohexylmethoxypurine scaffold. The computational results in this work show that the QM/MM interaction energy is strongly correlated to the biological activity and can be used as a predictor, at least within a family of substrates. A detailed analysis of the protein-ligand structures obtained from molecular dynamics simulations shows specific interactions within the active site that, in some cases, have not been reported before to our knowledge. The computed interaction …
Enthalpy/entropy compensation effects from cavity desolvation underpin broad ligand binding selectivity for rat odorant binding protein 3
2014
Evolution has produced proteins with exquisite ligand binding specificity, and manipulating this effect has been the basis for much of modern rational drug design. However, there are general classes of proteins with broader ligand selectivity linked to function, the origin of which is poorly understood. The odorant binding proteins (OBPs) sequester volatile molecules for transportation to the olfactory receptors. Rat OBP3, which we characterize by X-ray crystallography and NMR, binds a homologous series of aliphatic gamma-lactones within its aromatic-rich hydrophobic pocket with remarkably little variation in affinity but extensive enthalpy/entropy compensation effects. We show that the bin…