Abstract Details

Poster 11: Highly Soluble/Poorly Metabolized BDDCS Class 3 Drugs Share High Similarity with Small Peptides

Fabio Broccatelli1, Nathan Brown1, Cristian G. Bologa2, Jeremy J. Yang2, Tudor I. Oprea2, 3
1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, UK
2Translational Informatics Division, Department of Internal Medicine, MSC09 5025, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
3Center of Biological Sequence Analysis, Technical University of Denmark, Kemitorvet, Building 208, Lyngby 2800, Denmark
The strategies currently used in drug discovery programs will determine the future trends in the pharmaceutical industry and should therefore be guided, but not unduly biased, by past knowledge. The landscape leading to the implementation of physico-chemical guidelines for hit and lead optimization is evolving in response to new issues (e.g. toxicity), new directives from regulatory agencies and new technologies. Such guidelines are often interpreted as boundaries, defining a well-limited portion of the chemical space that for simplicity we refer to as the Ro5 (rule-of-five)-box [Adv. Drug Deliv. Rev., 1997, 23: 3-25]. Chemicals within this box are designed to tackle ADME issues exploiting passive processes; they must possess good permeability and solubility, acceptable plasma protein binding (PPB), acceptable metabolic and toxicity profile, and optimal off target activity. In this scenario, the limited number of protein targets that are druggable using Ro5 compliant compounds is a further restriction.
Outside the Ro5-box, new therapeutic categories emerge as blockbusters. In particular the number of oligopeptides in clinical trials (and approved drugs) has steadily increased over the last decade (e.g. Copaxone, Lupron, Zoladex, Sandostatin), validating the idea that unconventional approaches can lead to new drugs. From a chemical viewpoint, the main advantage of peptides as active pharmaceutical ingredients (APIs) is their high solubility. Small peptides are by definition metabolites, thus generally not processed by xenobiotic oxidative metabolism such as the P450 pathway, and have low PPB. Being outside the Ro5-box, the use of oligopeptides as APIs is likely to extend the number of targets that we consider druggable. The disadvantage of therapeutic oligopeptides is poor permeability and rapid clearance. Although these limitations could be addressed via formulation, oligopeptides are only suitable for extracellular targets, unless uptake transporters or endocytosis are involved. From a biopharmaceutic prospective, oligopeptides behave similarly to highly soluble, poorly permeable and metabolically stable compounds, which are categorized as class 3 BDDCS (Biopharmaceutics Drug Disposition Classification System) and BCS (Biopharmaceutic Classification System) compounds. APIs in this category are mostly absorbed in the gut through active uptake or paracellular transport, are not significantly metabolized, have low hepato- and cardiac toxicity and low PPB.
Our work explores the chemical determinants of the similarity between BDDCS/BCS class 3 drugs and the most elementary oligopeptide unit: dipeptides. Using our own models [Mol. Pharmaceutics, 2012, 9, 570-580], a BDDCS class prediction is performed for the 400 dipeptides that result by combining the 20 proteinogenic amino acids. Representative samples from the different BDDCS classes are compared in terms of Ro5 properties, 3D shape and electrostatics (ROCS) to the 400 dipeptides. The distribution of the highest pairwise similarities is analyzed.
Results show that class 3 APIs share high similarity to dipeptides. That is, BDDCS/BCS class 3 is an intermediate category in-between protein metabolites and xenobiotics. We hypothesize that, due to this similarity, class 3 compounds are not extensively metabolized via the P450 pathway and have low PPB. Furthermore, their lack of peptidic bonds avoids rapid clearance. Pharmacological studies could optimize the profile of new BDDCS class 3 chemicals to target specific proteins and uptake transporters, as a new rational strategy in drug discovery.

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