Human apurinic/apyrimidinic endonuclease-1 (APE-1) is essential for base excision repair and plays a major role in DNA repair and maintaining genomic stability. Cancer cells treated with conventional DNA-damaging agents develop resistance due in part to upregulation of enzymes i ...
Recent interest in inactive kinase conformations has generated the need to develop new biochemical tools to study them. Here, we describe the use of a fluorescent probe that selectively and potently binds to a specific inactive conformation of protein kinases. This allows for the thermody ...
Several protein kinases have been characterized in a specific inactive form called the DFG-out conformation. Unlike the active conformation which is conserved in all kinases, the inactive DFG-out conformation appears to be accessible to only certain kinases. This inactive conform ...
There is growing interest in exploring allosteric sites on proteins for drug discovery. At the center of the regulation of many protein kinases from the AGC family there is an allosteric site termed “PIF-pocket.” The regulated binding of a C-terminal region of the kinase to the PIF-pocket, within t ...
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS), the most common cancer in AIDS patients. All herpesviruses express a conserved dimeric serine protease that is required for generating infectious virions and is therefore of pharmac ...
Accumulating work over the past decade has shown that peptide aptamer screening represents a valid strategy for inhibitor identification that can be applied to a variety of different targets. Because of the screening method in cells and the highly combinatorial libraries available, th ...
Virtual ligand screening is a powerful technique to identify potential hits of targets and to increase hit rates. Here, we describe how we used this technique combined with NMR 15N HSQC experiments to obtain small molecules that bind to the PDZ domain of Dvl targeting the Wnt signaling pathway.
Small molecule docking and virtual screening of candidate compounds have become an integral part of drug discovery pipelines, complementing and streamlining experimental efforts in that regard. In this chapter, we describe specific software packages and protocols that can be used ...
RNA is unique in nanoscale fabrication due to its amazing diversity of function and structure. RNA nanoparticles can be fabricated with a level of simplicity characteristic of DNA while possessing versatile tertiary structure and catalytic function similar to that of proteins. A large v ...
MicroRNAs (miRNAs) are highly conserved small RNAs which regulate gene expression primarily through base pairing to the 3′ untranslated region of target messenger RNA (mRNA), leading to mRNA degradation or translation inhibition depending on the complementarity between the miRNA ...
The discovery of oncogenes and tumor suppressors as a driver of cancer development has triggered the development of target-specific small molecule anticancer compounds. As exemplified by Imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia-associated BCR/ ...
This chapter provides an overview of the Bayesian approach to data analysis, modeling, and statistical decision making. The topics covered go from basic concepts and definitions (random variables, Bayes’ rule, prior distributions) to various models of general use in biology (hierarc ...
The maximum likelihood method is a popular statistical inferential procedure widely used in many areas to obtain the estimates of the unknown parameters of a population of interest. This chapter gives a brief description of the important concepts underlying the maximum likelihood met ...
Partial least square (pls) methods (also sometimes called projection to latent structures) relate the information present in two data tables that collect measurements on the same set of observations. pls methods proceed by deriving latent variables which are (optimal) linear combin ...
Principal components analysis (PCA) is a standard tool in multivariate data analysis to reduce the number of dimensions, while retaining as much as possible of the data’s variation. Instead of investigating thousands of original variables, the first few components containing the majo ...
The fundamental and more critical steps that are necessary for the development and validation of QSAR models are presented in this chapter as best practices in the field. These procedures are discussed in the context of predictive QSAR modelling that is focused on achieving models of the highe ...
In this chapter we provide an overview of the basic theory of ordinary differential equations (ODE). We give the basics of analytical methods for their solutions and also review numerical methods. The chapter should serve as a primer for the basic application of ODEs and systems of ODEs in practice. As ...
Software agents are particularly suitable for engineering models and simulations of cellular systems. In a very natural and intuitive manner, individual software components are therein delegated to reproduce “in silico” the behavior of individual components of alive systems at a g ...
Comprehensive gene expression analysis has been applied to investigate the molecular mechanism of toxicity, which is generally known as toxicogenomics (TGx). When analyzing large-scale gene expression data obtained by microarray analysis, typical multivariate data analy ...
Use of predictive technologies is an important aspect of many efforts in today’s research, development, and regulatory landscapes. Computational methods as predictive tools for supporting drug safety assessments is of widespread interest as the field of in silico assessments rapi ...
