The application of molecular topology for ulcerative colitis drug discovery

ABSTRACT

Introduction: Although the therapeutic arsenal against ulcerative colitis has greatly expanded (including the revolutionary advent of biologics), there remain patients who are refractory to current medications while the safety of the available therapeutics could also be improved. Molecular topology provides a theoretic framework for the discovery of new therapeutic agents in a very efficient manner, and its applications in the field of ulcerative colitis have slowly begun to flourish.

Areas covered: After discussing the basics of molecular topology, the authors review QSAR models focusing on validated targets for the treatment of ulcerative colitis, entirely or partially based on topological descriptors.

Expert opinion: The application of molecular topology to ulcerative colitis drug discovery is still very limited, and many of the existing reports seem to be strictly theoretic, with no experimental validation or practical applications. Interestingly, mechanism-independent models based on phenotypic responses have recently been reported. Such models are in agreement with the recent interest raised by network pharmacology as a potential solution for complex disorders. These and other similar studies applying molecular topology suggest that some therapeutic categories may present a ‘topological pattern’ that goes beyond a specific mechanism of action.

KEYWORDS:

• Ulcerative colitis
• inflammatory bowel disease
• drug discovery
• molecular topology
• topological indices
• molecular descriptors
• QSAR
• virtual screening

Article highlights

• Currently approved treatments against ulcerative colitis have been discovered through immunological studies. The number of studies addressing the discovery of drug candidates using computer-aided methodologies is still scarce. Molecular Topology might be the dominant approach for ligand-based approximations in the field of ulcerative colitis computer-aided drug discovery.

• Molecular Topology, jointly with QSAR, can be applied to explore the ever growing chemical space in a very efficient manner.

• Topological indices are graph-invariant descriptors obtained from chemical graphs by algebraic operations. They are, in general, conformation- and orientation-independent (thus, no geometry optimization of any sort is required to obtain their values). Generally speaking, they are insensitive to geometric and space isomers.

• Applications of Molecular Topology in different fields of drug discovery suggest that, independently of their particular mechanisms of action, drugs that belong to a given therapeutic category tend to share similar topologies.

• Among the many QSAR studies that use molecular topology to identify novel drug candidates for ulcerative colitis, a considerable number of articles report models that include topological autocorrelations weighted by different atomic properties (e.g. electronegativity, Van der Waals volumes). Interestingly, those descriptors are strongly related with the pharmacophore concept, but from a topological perspective instead of a space geometric one.

• Being a complex disease, ulcerative colitis should be approached from network based pharmacology perspective. QSAR models that model phenotypic responses (e.g. activity in an in vivo model of colitis) could prove very useful to find novel effective treatments.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors are members of the Argentinian National Scientific and Technical Research Council (CONICET) and are researchers at the National University of La Plata (UNLP). These institutions fund the authors work.