|Effective Use of In-Silico Tools in Lead Optimization|
Pranas Japertas, Andrius Sazonovas and Kiril Lanevskij
Of all the challenges facing medicinal chemists in general, one of the most significant must be transforming an active molecule into a viable drug. Lead optimization efforts are guided by a combination of factors, such as potency, ease of synthesis, patentability concerns, specific synthetic constrains of the interaction with the target, as well as the lead’s toxicity and ADME properties.
|A Weight-of-Evidence Approach to Prioritisation based on Consensus across Multiple Sources of Information|
Roman Affentranger (1), Barry Hardy (1), Glenn Myatt (2), Nina Jeliazkova (3), Matthew Clark (4), Jeffrey Wiseman (4)
We present the results of initial work carried out within the OpenToxLink Virtual Organization, applying a Weight-of-Evidence (WoE) approach based on consensus across multiple sources of information for the prediction of adverse effects of a large set of potential antimalarial compounds. The work was carried out as part of the EU FP7 project SYNERGY, evaluating the support of decision dashboards and event-driven collaborative research of software developed within SYNERGY.
|Three-dimensional quantitative structure-activity relationship analysis and ADME predictions of guanylhydrazone coactivator binding inhibitors of estrogen receptors|
Sergey Shityakov, Thomas Dandekar
The estrogen receptors (ER) refer to a group of the nuclear hormone receptor superfamily of ligand-mediated transcriptional factors. Over expression of this type of receptors leads to a breast cancer progression. Hormone-responsive breast cancer develops resistance to conventional anti-cancer therapy, and this becomes a major problem in a breast cancer therapy.
|New Approach for In Silico Genotoxicity Testing of Impurities and Degradants|
Kiril Lanevskij, Liutauras Juska, Remigijus Didziapetris and Pranas Japertas
This study presents a novel approach to aid this assessment based on probabilistic predictors of mutagenicity in Ames test and binding to Estrogen Receptor, supplemented by a knowledge-based system of structural alerts.
|In silico Identification of Metabolic Soft Spots: Case Study Using ACD/ADME Suite Software|
Justas Dapkunas, Andrius Sazonovas, Remigijus Didziapetris and Pranas Japertas
Metabolic stability, determined in liver microsomes, is one of the primary assays used in early drug discovery. A key factor limiting compound half-life is the cytochrome P450 mediated metabolism. High clearance by these enzymes implies a higher and more frequent dosing as well as poses a risk for individual variations in exposure.
|Differential Toxicities of Kinase Inhibitors (KI) on Bone Marrow Progenitors from Different Species|
Clarke, E. and Dos Santos, G.
Myelotoxicity is often a side effect of kinase inhibitors. We reported a correlation (R2 = 0.81) between in vitro human CFU-GM IC50 values and clinical neutropenia. When these values were obtained from other species, non-human primate and dog values compared well with human data, but rat and mouse IC50 values differed significantly. This suggests rodent assays may not accurately predict toxicity to the human hematopoietic system.
|Development of Two Novel High-throughput Colorimetric Toxicity Detection Assays|
Kimberly Lubell and Joseph Krebs
The MaxDiscovery Aspartate Transaminase (AST) and Lactate Dehydrogenase (LDH) Color Endpoint Assays permit visible detection of in vivo toxicity using only 5 µL of serum from rodents or other mammals. These novel assays employ simplified endpoint analysis to offer high sensitivity, low detection limits and the ability to use a visible plate reader.
|The use of the IV microtracer technique to drive formulation optimisation|
Vanessa Zann, Paul Dickinson, Wang Wang Lee, George Kirk, Owen Jones, Andy Gray, Davindera Singh Sanghera, Mark Seymour, Jo Collier, Lloyd Stevens, Julie Dent
Strategy: Use IV microtracer techniquer to de risk compounds with PK issues and drive formulation development
|Addressing the challenges of poor solubility: Rapid development and clinical evaluation of a lipid based formulation to enhance oral bioavailability of amuvatinib (MP-470)|
P.D. Scholes, J. McDermott, J. Vertommen, J-L Colin, G Choy, M Azab, R Joshi and S. Redkar
Physiochemical and biopharmaceutical properties of new chemical entities are presenting increasing challenges to successful oral drug delivery. Here we present data on amuvatinib, a novel multi-targeted tyrosine kinase inhibitor specifically designed to be a potent inhibitor of mutant c-Kit and PDGFRalpha.