Current Drug Discovery Technologies - Volume 4, Issue 3, 2007

Chemical breakthrough generates large numbers of prospective drug molecules; the use of ADMET (absorption, distribution, metabolism, excretion and toxicity) properties is flattering progressively more imperative in the drug discovery, assortment, development and promotion processes. Due to the inauspicious ADMET properties a huge amount of molecules in the development stage got failure. In the past years several authors reported that it possible to do some prediction of the ADMET properties using the structural features of the molecules, suing several approaches. One of the most important approaches is QSAR modeling of the data derived from their activity profiles and their different structural features (i.e., quantitative molecular descriptors). This review is critically assessing some of the most important issues for the effective prediction of ADMET properties of drug candidates based on QSAR modeling approaches.

This study sought to assess by computer modeling the interactions between dentinal collagen and primer monomer ligands used to promote bonding of restorations to tooth. Modeling was carried out both by direct and indirect methods to probe interaction mechanisms. Ligands studied in this investigation conformed chemically to methacrylate phosphates of alkane diol, with changes in the number of methylene spacer groups. Increase in number of methylene groups in the series introduces increasing levels of ligand conformational freedom. An automatic docking program was used to analyze the effect of these changes on primer-collagen interactions in direct (target-based) modeling. The effect of limited modifications of amino acid residue sequences in structural variants of type 1 dentinal collagen was also assessed in this approach. The indirect (ligand-based) modeling used a pharmacaphore search to mimic primer binding to type 1 collagen using a common functional alignment algorithm. Docking energy, and the non-bonded and electrostatic contributions to it, showed statistically highly significant differences (p<0.0001) with ligand conformational freedom. But the effect of collagen composition differences was, although statistically significant (p<0.05), relatively small. Both targetbased direct docking and ligand-based indirect modeling visualizations showed that conformations tended to align in a 3- D geometric pattern in bound states, and that the conformational flexibility of the ligands played a critical role in alignment. The results suggest that incorporation of spacer groups in primer monomers may modify dentin bonding to improve overall adhesion under optimum conditions..

Thrombocytopenia is a frequent finding in several clinical settings, including bone marrow failure associated with various disorders, immune-mediated thrombocytopenia, and chronic liver diseases. Currently, there is an unmet need for thrombopoietic agents to treat this condition. Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor that is expressed on the surface of megakaryocytes and megakaryocytic precursors. Although clinical trials with first generation thrombopoietic agents were abruptly discontinued after the development of TPO autoantibodies had been observed, non-antigenic second generation thrombopoietic growth factors with unique pharmacological properties have been developed. These include TPO peptide mimetics (AMG 531 and Fab59), TPO nonpeptide mimetics (eltrombopag, NIP-004, and AKR-501) and TPO agonist antibodies. All of these bind to and activate the TPO receptor in different ways but all via JAK2/STAT signalling pathways, producing a dose-dependent rise in platelet counts. In view of their use as therapeutic agents, nonpeptide agonists seem to have an advantage over peptide agonists, in that they could be orally bioavailable. The aim of the present review is to illustrate the biology of TPO and its receptor, and to describe the structure and function of the new thrombopoietic agents.

Survivin, a member of the IAP family is an attractive target for cancer treatment due to it's over expression in most cancers and low or no expression in most differentiated adult tissues. Survivin expression is a poor prognostic marker in a number of cancers. Clinical trials are currently underway evaluating anti-sense oligonucleotides against Survivin, immunotherapy using Survivin primed dentritic cells and peptide mimics that block interaction of Survivin with Hsp90 resulting in loss of Survivin protein stability. Additional approaches using ribozymes against Survivin mRNA, or dominant-negative cDNA to block Survivin function are in pre-clinical stages. Like many genes, Survivin is alternately spliced and a number of new splice variants have recently been identified. Expression of some of these splice variants correlates with loss of steroid receptors as well as the tumor suppressor p53, in some cancers, suggesting that like wild-type Survivin, at least some of these splice variants may also have prognostic relevance. This review will focus on the current understanding of the function of Survivin splice variants and their expression and sub-cellular localization in normal and neoplastic tissues as well as critically evaluating the potential toxicity of the Survivin directed therapies and their predicted effect on the alternatively spliced Survivin isoforms. Supported by grants HL69669 and HL79654 to L.M.P from the National Institutes of Health.

Omeprazole (OME), a proton pump inhibitor used to treat acid reflux disease and gastric ulcers presents a formulation challenge due to its rapid decomposition at acidic and neutral pHs. Thus, the aim of this project was to investigate whether interaction with sulfobutylether-β-cyclodextrin (Captisol®-CD) could improve omeprazole stability and provide more efficient oral liquid formulations. A stability-indicating high performance liquid chromatography assay allowed for the quantitation of S- and R-forms of OME in the presence and absence of Captisol®-CD. The developed method was validated to discriminate between OME and its degradation products and used to describe the kinetic model of OME at different pH values over a period of 36 days. Calculated degradation constants (kobs), were directly correlated with the H+ concentrations of the solutions regardless of whether the omeprazole was complexed with the Captisol®-CD or not. Moreover, the pH-rate profile curve indicated that in all cases, maximum stability was achieved at pH 11. Though it was anticipated that interaction of OME with Captisol ®-CD might increase the relative stability of OME at a lower pH, the cavity of the cyclodextrin was too small to allow the inclusion to occur. However the R-isomer of OME, both in the presence or absence of the cyclodextrin appeared to be slightly less stable than the corresponding S-form at the same pH conditions.

A series of new C-3 and N1-substituted 4-fluorotryptamides have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT1 and MT2 melatonin receptor subtypes expressed in NIH 3T3 cells. Planar sp2 geometry at C-3-βC seems to decrease the population of the preferred conformation as it renders 4-fluoroindoles 4b-d weaker antagonists than their C-3-βC-unsubstituted congeners 3a-e. This effect is not preclusively linked with the C-3 region, as the same geometry around N1 (compounds 5a-c) similarly leads to weak antagonistic action. Last, the new C-3 substituted 4-fluorotryptamides presented herein are substantially more potent than their respective N-OMe functionalized congeners, previously reported.

Cervical cancer is the second most common malignancy in women worldwide. Two HPV strains, HPV-16 and 18, occur in the 70% of untreated cancers. Expression of viral oncogenes E6 and E7 disrupt the cell cycle by interfering with p53 and p107Rb. It is known that HPV infection is necessary but insufficient to cause malignancy. Furthermore, persistence of HPV-16 or 18 in women does not necessarily result in cancer. Persistence indicates the importance of other factors for malignant conversion of high-grade HPV infection. The multi-step cervical carcinogenesis process is amendable to molecular therapeutics such as therapeutic nucleic acids (TNAs). TNA-based therapies for cervical carcinoma include ribozymes, antisense oligonucleotides (AS-ODNs) and small interfering RNAs (siRNAs). In vitro experiments with TNAs successfully inhibited E6/E7 expression and caused induction of apoptosis and/or senescence in cervical carcinoma cells. Early ribozyme and AS-ODN approaches showed promise as therapeutic moieties for cervical cancer. Despite the very high in vitro efficiency of siRNA-based therapies they present the same issues that burdened clinical development of ribozymes and AS-ODNs. These issues include intracellular target accessibility, specificity and delivery. Ribozymes are useful for functional genomic studies including diagnosis. Moreover, AS-ODNs appear better suited for clinical protocols because recent advances in nucleic acid chemistry allow higher cell uptake with very low off-target effects leading to actual AS-ODNs clinical applications. By using combined treatments with multiple targets it will be possible to apply TNAs directly to the cancerous cervix to destroy viral RNA and obliterate the tumor.