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A fast new algorithm (Fingerprints for Ligands And Proteins or FLAP) able to describe small molecules and protein structures using a common reference framework of four-point pharmacophore fingerprints and a molecular-cavity shape is described in detail. The procedure starts by using the GRID force field to calculate molecular interaction fields, which are(More)
MDM2 and MDMX are oncogenic homologue proteins that regulate the activity and stability of p53, a tumor suppressor protein involved in more than 50% of human cancers. While the large body of experiments so far accumulated has validated MDM2 as a therapeutically important target for the development of anticancer drugs, it is only recently that MDMX has also(More)
Given the three-dimensional structure of a protein, how can one find the sites where other molecules might bind to it? Do these sites have the properties necessary for high affinity binding? Is this protein a suitable target for drug design? Here, we discuss recent developments in computational methods to address these and related questions. Geometric(More)
Tautomeric rearrangements affect the results of cheminformatics applications that depend on the knowledge of the 2D or 3D structure of a compound, such as tools for database searches, fingerprint generation, virtual screening, and physical-chemical properties prediction. In this paper we present TauThor, a tool to enumerate tautomers and predict tautomer(More)
A new computational algorithm for protein binding sites characterization and comparison has been developed, which uses a common reference framework of the projected ligand-space four-point pharmacophore fingerprints, includes cavity shape, and can be used with diverse proteins as no structural alignment is required. Protein binding sites are first described(More)
Many heterocyclic amines (HCA) present in cooked food exert a genotoxic activity when they are metabolised (N-oxidated) by the human cytochrome P450 1A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the basis of models of HCA-CYP1A2h complexes. The CYP1A2h enzyme(More)
One of the most important physicochemical properties of a molecule is pKa. It is known that two parameters imperative in ADME profiling, solubility, and lipophilicity are governed by pKa, and receptor binding can be influenced by pKa. Because most drugs are ionized in physiological conditions, pKa is particularly relevant to medicinal chemistry. Despite the(More)
Pharmacophore elucidation approaches are routinely used in drug discovery, primarily with the aim of determining the three-dimensional arrangement of common features shared by ligands interacting at the site of interest; these features can then be used to investigate the structure-activity relationship between the ligands and also to screen for other(More)
The design and optimization of small molecule inhibitors of the murine double minute clone 2-p53 (p53-MDM2) interaction has attracted a great deal of interest as a way to novel anticancer therapies. Herein we report 3D-QSAR studies of 41 small molecule inhibitors based on the use of molecular interaction fields and docking experiments as part of an approach(More)
Cocaine is one of the most widely abused drugs in the industrial world. Substantial evidence has accumulated that the dopamine transporter (DAT) is a key target for cocaine regarding its reinforcing effects. This work describes the application of chemometric methods to a data set of 54 N(1)-benzhydryl-oxy-alkyl-N(4)-phenyl-alk(en)yl-piperazines (GBR(More)