Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
RNA folding follows a hierarchical pathway analogous to that observed for proteins. The primary base sequence dictates the type of secondary structure formed, which in turn allows the formation of a possible tertiary structure via interaction of preformed secondary structures. Formation of RNA secondary structure dominates the free energy of folding, as each base pair contributes 1–3 kcal/mol of free energy to the final fold. For example, transfer RNAs (tRNAs) have a uniquely evolved tertiary structure, and their primary sequence directs a “clover leaf” secondary structure composed of three stem-loop segments. However, the well-known three-dimensional structure of tRNAs is finalized by the interaction between two of the hairpin loops (the T- and C-loops). This last step, the formation of tertiary structure, contributes only 1.5 kcal/mol of free energy. With regard to small molecule targeting, the secondary structure is generally regarded as the key determinant in defining the “druggability” of a particular RNA.
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
To address the failure rate between ligand and drug, many computational approaches have been developed for the optimization of druggability, blood-brain barrier penetration, lipophilicity, and metabolism. All the computational approaches contribute to more cost-effective discovery and optimization of compounds, accelerating progress toward the clinic. Such high-throughput methods with the power to consider multiple targets at the same time are particularly effective and useful for designing multi-target drugs as will be considered in the next section.
A Novel Compound Plumercine from Plumeria alba Exhibits Promising Anti-Leukemic Efficacies against B Cell Acute Lymphoblastic Leukemia
Published in Nutrition and Cancer, 2022
Aaheli Chatterjee, Amrita Pal, Santanu Paul
The success of Drug development or drug designing is highly conditioned by the characteristics of the targets used (44). It is generally predicted by its affinity to interact with drugs that are supposed to provide some therapeutic benefits (45). Druggability can also be predicted based on the properties of ligand or the drug binding and is known to be ligand based druggability. This is mainly done for biotherapeutic reagents (46) Druggability properties include factors like Lipinski’s rule of five violations, Solubility Forecast Index, QEDw score etc. According to Lipinski’s rule of five violations for an orally active drug there should not be more than one violation of the five rules. As observed in Table 3, Plumericine and Isoplumercine have shown 0 violation to Lipinski’s rule of five violations which brings out the fact about their good druggability. On the other hand 13-O-p-Coumaroylplumieride has shown two violations which are considered to be a negative aspect toward drug development. Similar type of results is shown by Veber Rule and Egan rule which predicts the oral bioavailability of the compounds. Plumericine and Isoplumericine have shown good results compared to 13-O-p-Coumaroylplumieride. Though all of the given compounds show good solubility index, the chances to become potential drug candidate is observed more in case of Plumericine and Isoplumercine depending on their druggability properties. Different druggability properties of Plumercine, Isoplumericine and 13-O-p-Coumaroylplumieride are listed in Table 3.
Non-human primates in the PKPD evaluation of biologics: Needs and options to reduce, refine, and replace. A BioSafe White Paper
Published in mAbs, 2022
Karelle Ménochet, Hongbin Yu, Bonnie Wang, Jay Tibbitts, Cheng-Pang Hsu, Amrita V. Kamath, Wolfgang F. Richter, Andreas Baumann
During drug development, it is often necessary to determine whether a target is “druggable”. The druggability of a target can be related to a number of characteristics, including tissue distribution or location, and expression and turnover. Drug targets with high levels of expression and/or turnover, particularly in non-target tissues can pose challenges due to the high amounts of drug required to sustain sufficient levels of occupancy to drive the desired pharmacologic effects. An excellent example of this is CCL21, a soluble chemokine believed to play a role in modulating inflammation. QBP359 is a human IgG1 mAb that binds specifically to human CCL21 and cross-reacts with cynomolgus monkey, but not with mouse CCL21.60, 61 The similarity in binding of QBP359 between NHP and humans, and the physiologic similarities between these species, made the NHP a suitable system to explore the PKPD of this novel biotherapeutic for the purposes of estimating human efficacious dose. In a dose-range finding NHP toxicology study, the elimination rate of QBP359 was found to be rapid compared to a typical IgG and decreased as the dose increased, suggesting that CCL21 occupancy was not achieved at the low dose used in that study (10 mg/kg weekly). This raised questions about the ability of QBP359 to sufficiently suppress CCL21 concentrations at manageable doses. Subsequent PK and biodistribution studies in the NHP were conducted to enable a more complete assessment of the PK of QBP359 and the dynamics of CCL21 turnover, and information on the tissue localization of CCL21.
ATAD2 in cancer: a pharmacologically challenging but tractable target
Published in Expert Opinion on Therapeutic Targets, 2018
Muzammal Hussain, Yang Zhou, Yu Song, H.M. Adnan Hameed, Hao Jiang, Yaoquan Tu, Jiancun Zhang
A protein is considered to be a ‘druggable’ target when its activity can be modulated by a drug, either a small-molecule ligand or a biological [60,61]. Theoretically, a target protein’s druggability can be evaluated by different approaches, including: the existence of a small-molecule binding domain, the presence of an extracellular domain (for biological targeting), the availability of 3D crystal structure, and the feasibility of high-throughput assays [60]. Moreover, given the 3D structure, different computational approaches, described elsewhere [62], have been developed to identify and characterize a target protein’s binding sites for ligand design or discovery. Looking from the perspective of ATAD2, the presence of two functional domains (BRD and the AAA ATPase domain), which could potentially be targeted by small-molecule inhibitors [63–65], deems it to be a ‘druggable’ target. Likewise, several 3D structures characterizing ATAD2’s BRD are available both in free or complex form in the Protein Data Bank (PDB), which have successfully been employed for computational druggability assessment and drug discovery studies [13,14]. In the following sections, we summarize the current druggability prospects as well as the drug discovery progress that has been made to date in targeting ATAD2’s BRD and AAA ATPase domains.
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