Biomedical subjects

Giuseppe Ermondi

Publications and source records attributed to Giuseppe Ermondi.

8 recordsLinked to original sources

PubMed2006

Recognition forces in ligand-protein complexes: blending information from different sources.

A variety of ligands interact with proteins in many biological processes; shape complementarity, electrostatic forces and hydrophobicity are the main factors governing these interactions. Although this is accepted by the scientific community, confusion about the significance of certain terms (e.g. hydrophobicity, salt bridge) and the difficulty of discussing the balance of acting forces rather than their single contributions, are two of the main problems encountered by researchers working in the field. These difficulties are sometimes enhanced by the unskilled use of informatics tools, which give great help in understanding the topic (especially from the visual standpoint), but only if used critically. After explaining some general chemical concepts, the commentary discusses the main forces governing ligand-protein interactions, focusing on those generating confusion among scientists with different backgrounds. Three examples of ligand-protein interactions are then discussed to illustrate the advantages and drawbacks of some in silico tools, highlighting the main interactions responsible for complex formation. The same examples are used to point out the limits in separating forces that are mandatory for occurrence of a given interaction and additional forces.

Chemical Phenomena↗

PubMed2006

Classification of alpha-cyclodextrins inclusion complexes into Type 1 and Type 2: a prelude to log K prediction.

Molecular Interaction Fields (MIFs) were used in combination with a small number of geometrical descriptors to separate nine alpha-CD complexes into Type 1 and Type 2, two classes, respectively, containing complexes having high log K and low log K values (stoichiometry of 1:1). Calculations were performed on the crystallographic conformations of alpha-CDs after their separation from the ligand and without minimization. The results show that the computational strategy adopted is able to distinguish Type 1 from Type 2 complexes and that it can be applied to all CD families.

Carbohydrate Conformation↗

PubMed2006

A combined in silico strategy to describe the variation of some 3D molecular properties of beta-cyclodextrin due to the formation of inclusion complexes.

A powerful in silico strategy based on the combined use of two computational tools (MLP and MIFs) able to calculate and visualize 3D molecular fields can give useful information about surface properties of macromolecules involved in the mechanisms of formation of complexes. In particular, this study investigated the variation in polar/hydrophobic pattern induced on the beta-CD alone (i.e. =without the ligand) by the inclusion of four ligands having different lipophilicities and small size. Results indicate that, in the presence of guests with P>0, the hydrophobicity of beta-CD increases in the cavity and its surroundings on the primary face.

Databases, Protein↗

PubMed2005

Calculating virtual log P in the alkane/water system (log P(N)(alk)) and its derived parameters deltalog P(N)(oct-alk) and log D(pH)(alk).

Growing interest in the use of both the logarithm of the partition coefficient of the neutral species in the alkane/water system (log P(N)(alk)) and the difference between log P(N)(oct) (the logarithm of the partition coefficient of the neutral species in the n-octanol/water system) and log P(N)(alk) (Deltalog P(N)(oct-alk)) in the early stages of drug design has stimulated development of a computational tool based on the Volsurf software to predict virtual (=of each conformer) log P(N)(alk) and virtual log P(N)(oct). From these two pieces of data, it is then possible to calculate Deltalog P(N)(oct-alk) for a given compound as the difference between log P(N)(oct) and log P(N)(alk). Once the pK(a) is known and the legitimacy of neglecting the contribution made by the ionized species has been checked, it is also possible to calculate log D(pH)(alk), which might be an important lipophilicity descriptor in absorption, distribution, metabolism, and excretion (ADME) prediction, from log P(N)(alk).

1-Octanol↗

PubMed2004

Ionization, lipophilicity, and molecular modeling to investigate permeability and other biological properties of amlodipine.

This paper uses a recent approach toward drug discovery, in which in silico tools and experimental data are combined together to study the structural features of amlodipine and their relevance in the peculiar pharmacodynamic and pharmacokinetic profiles of this long acting calcium antagonist. Results reveal for amlodipine two families of conformers (folded and extended) but also demonstrate that protonation is the predominant factor governing amlodipine intermolecular interactions among which ionic forces play a major role.

Amlodipine↗

PubMed2004

Contribution of ionization and lipophilicity to drug binding to albumin: a preliminary step toward biodistribution prediction.

Understanding the molecular mechanisms governing albumin binding is a major challenge in absorption-distribution-metabolism-excretion prediction. To gain insight into this complex field, an ultracentrifugation method to measure the drug fraction bound to bovine serum albumin [%B(DAB)] is presented. The second part of the study shows the dependence of the experimental binding parameter on ionization and lipophilicity descriptors (pK(a) and log D(oct)(7.4) for a series of 14 structurally diverse drugs. Finally, a docking strategy is used to rationalize the findings; the results confirm the mostly nonspecific nature of the interaction of albumin with neutral ligands.

Chromatography, Affinity↗

PubMed2004

Docking studies on NSAID/COX-2 isozyme complexes using contact statistics analysis.

The selective inhibition of COX-2 isozymes should lead to a new generation of NSAIDs with significantly reduced side effects; e.g. celecoxib (Celebrex) and rofecoxib (Vioxx). To obtain inhibitors with higher selectivity it has become essential to gain additional insight into the details of the interactions between COX isozymes-and NSAIDs. Although X-ray structures of COX-2 complexed with a small number of ligands are available, experimental data are missing for two well-known selective COX-2 inhibitors (rofecoxib and nimesulide) and docking results reported are controversial. We use a combination of a traditional docking procedure with a new computational tool (Contact Statistics analysis) that identifies the best orientation among a number of solutions to shed some light on this topic.

Algorithms↗

PubMed2003

A comparison of calculated and experimental parameters as sources of structural information: the case of lipophilicity-related descriptors.

This review is organized in three parts: firstly there is a general overview of recent developments in lipophilicity written to induce medicinal chemists to question what they want to obtain from this kind of study; secondly, the state-of-the-art of experimental and computational determination of log P is briefly reviewed; finally, some applications are discussed to illustrate how much information can be extracted from lipophilicity, and to highlight the difficulty of obtaining a reliable, general method to work with.

Chemical Phenomena↗