Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery

GPCR modeling approaches are widely used in the hit-to-lead (H2L) and lead optimization (LO) stages of drug discovery. The aims of these modeling approaches are to predict the 3D structures of the receptor-ligand complexes, to explore the key interactions between the receptor and the ligand and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this book chapter, we present a brief survey of key computational approaches integrated with hierarchical GPCR modeling protocol (HGMP) used in hit-to-lead (H2L) and in lead optimization (LO) stages of structure-based drug discovery (SBDD). We outline the differences in modeling strategies used in H2L and LO of SBDD and illustrate how these tools have been applied in three drug discovery projects

From protein sequences to 3D-structures and beyond: the example of the UniProt Knowledgebase

With the dramatic increase in the volume of experimental results in every domain of life sciences, assembling pertinent data and combining information from different fields has become a challenge. Information is dispersed over numerous specialized databases and is presented in many different formats. Rapid access to experiment-based information about well-characterized proteins helps predict the function of uncharacterized proteins identified by large-scale sequencing. In this context, universal knowledgebases play essential roles in providing access to data from complementary types of experiments and serving as hubs with cross-references to many specialized databases. This review outlines how the value of experimental data is optimized by combining high-quality protein sequences with complementary experimental results, including information derived from protein 3D-structures, using as an example the UniProt knowledgebase (UniProtKB) and the tools and links provided on its website (http://www.uniprot.org/). It also evokes precautions that are necessary for successful predictions and extrapolations

Histamine receptor activation by unsaturated (allyl and propargyl) homologs of histamine

The spectrum of agonist activity for three new homologs of histamine (cis- and trans-imidazolylallylamine and imidazolylpropargylamine) was evaluated in the isolated guinea pig ileum and right atrium. The homologs were about three log units less potent than histamine in stimulating contractions of the longitudinal muscles of the ileum, but they were histamine-like, pharmacologically, because they were sensitive to blockade by pyrilamine and resistant to blockade by atropine. In the right atrium, these weak agonists were partially sensitive to blockade by cimetidine. The agonist activity of the cis-isomer in particular was completely blocked by a combination of cimetidine and propranolol, but resistant to reserpine treatment (neuronal catecholamine depletion). Therefore, these homologs of histamine have the ability to stimulate H 1 - and H 2 -histamine receptors and beta -adrenoreceptors in vitro .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44880/1/11_2005_Article_BF01966582.pd

A horizontal alignment tool for numerical trend discovery in sequence data: application to protein hydropathy.

PMC3794901An algorithm is presented that returns the optimal pairwise gapped alignment of two sets of signed numerical sequence values. One distinguishing feature of this algorithm is a flexible comparison engine (based on both relative shape and absolute similarity measures) that does not rely on explicit gap penalties. Additionally, an empirical probability model is developed to estimate the significance of the returned alignment with respect to randomized data. The algorithm's utility for biological hypothesis formulation is demonstrated with test cases including database search and pairwise alignment of protein hydropathy. However, the algorithm and probability model could possibly be extended to accommodate other diverse types of protein or nucleic acid data, including positional thermodynamic stability and mRNA translation efficiency. The algorithm requires only numerical values as input and will readily compare data other than protein hydropathy. The tool is therefore expected to complement, rather than replace, existing sequence and structure based tools and may inform medical discovery, as exemplified by proposed similarity between a chlamydial ORFan protein and bacterial colicin pore-forming domain. The source code, documentation, and a basic web-server application are available.JH Libraries Open Access Fun

Applications of fluorescence and bioluminescence resonance energy transfer to drug discovery at G protein coupled receptors

The role of G protein coupled receptors (GPCRs) in numerous physiological processes that may be disrupted or modified in disease makes them key targets for the development of new therapeutic medicines. A wide variety of resonance energy transfer (RET) techniques such as fluorescence RET and bioluminescence RET have been developed in recent years to detect protein–protein interactions in living cells. Furthermore, these techniques are now being exploited to screen for novel compounds that activate or block GPCRs and to search for new, previously undiscovered signaling pathways activated by well-known pharmacologically classified drugs. The high resolution that can be achieved with these RET methods means that they are well suited to study both intramolecular conformational changes in response to ligand binding at the receptor level and intermolecular interactions involving protein translocation in subcellular compartments resulting from external stimuli. In this review we highlight the latest advances in these technologies to illustrate general principles

Implementation of the GAUSSIAN 78 programs on the NYU VAX/11-780: a probe into basis set and correlation effects on the structure of molecular complexes. [Complexes of p- and m-hydroxylaniline with formamidinium cation]

The program package is used in a theoretical study of molecular complexes that serve as models of drug receptor interactions. The complexes are of para-hydroxyaniline and meta-hydroxyaniline with formamidinium cation. Results indicate that the description of the nature of interaction obtained at the STO-3G SCF level does not change when the basis set is extended to the 4-31G level or when correlation effects are included to second order in a Moeller-Plesset formulation. 5 figures, 4 tables. (DLC

Ab initio effective potentials for atoms of the first three rows of the periodic table. [Tables, coreless Hartree--Fock effective potential]

The coreless Hartree--Fock effective potential (CHFEP) method is used to replace the core orbitals for atoms of the first three rows of the periodic table. Self-consistent field (SCF) calculations indicate that these effective potentials give Hartree--Fock quality orbitals and orbital energies. Optimized small basis sets for use with these effective potentials are presented along with some tests of these basis sets. It is seen that the effective potential allows one to use such small basis sets without the introduction of any serious error. These smaller basis set calculations allow for great savings in computational time and cost. (auth

Neonatal diabetes mellitus and congenital diaphragmatic hernia: coincidence or concurrent etiology?

<p>Abstract</p> <p>Neonatal diabetes mellitus (NDM) is a rare metabolic disorder, affecting approximately 1 in 500,000 live births. The management of NDM is challenging, as the benefits of controlling hyperglycemia must be balanced with the risks of iatrogenic hypoglycemia. NDM occurs in both permanent and transient forms, which have been genetically and phenotypically well characterized. Herein, we present the previously unreported combination of transient NDM (TNDM) and congenital diaphragmatic hernia (CDH). In addition to reviewing the management and genetics of NDM we discuss the potential for overlapping genetic or embryologic abnormalities to explain the concurrence of CDH and NDM.</p