Novel Pyrimethamine Based Anti-protozoan Agents Utilizing Isostere and Heuristic Structure-similarity Search | Chapter 04 | Advances in Applied Science and Technology Vol. 5
Aims:
To generate new medicaments for control and treatment of the parasitic
protozoan Toxoplasma gondii.
Study
Design: Structure similarity search and
isostere search was conducted over a broad range of structure categories.
Correlation and highest similarity scores were implemented to select the best
drug candidates.
Place and
Duration of Study: University of Nebraska, Department of
Chemistry, Durham Science Center, 6001 Dodge Street, Omaha Nebraska 68182, from
June 2016 to February 2017.
Methodology:
Utilizing pyrimethamine as the parent compound, a broad range of similar
structures and isosteres were found by applying search methods. The compounds
having the highest correlation and similarity scores were selected for the
study of molecular properties. The molecular properties were determined and
examined for underlying relationships by pattern recognition hierarchical
cluster analysis and K-means cluster analysis.
Results:
Thirty compounds were identified to have a very high level of structure
similarity or isosteric relationship to pyrimethamine. The molecular structures
and molecular properties are presented for all compounds, inclusive of
pyrimethamine. Hierarchical cluster analysis and K-means cluster analysis
indicated compounds with highest underlying similarity to pyrimethamine. Box
plots showed the over-all distribution of important pharmaceutical properties,
such as molecular weight, Log P, polar surface area, number of rotatable bonds,
molecular volume, and number of hydrogen bond donors. Structure components are
compared to elucidate potential clinical activity. Multiple regression is
applied on all compounds to generate a numerical relationship for prediction of
similar compounds. Save for only one
isostere, all compounds showed
zero violations of
the Rule of
5, indicating favorable
drug-likeness and bioavailability.
Conclusion:
Thirty compounds highly analogous to pyrimethamine were identified following
heuristic search course. The molecular properties were determined for all
compounds and indicated genuine potential
for treatment of toxoplasmosis. Correlation
of structure and
pattern recognition methods
indicated 30 compounds of clinical potential and property analogy to
pyrimethamine. All compounds in this study showed favorable bioavailability,
having zero violations of the rule of 5. Hierarchical cluster analysis and
K-means cluster analysis
showed that the
isostere compounds were
most similar to pyrimethamine. Multiple regression
analysis produced a mathematical model for predicting properties of compounds
of similar medicinal use. The study and design of new medicinal agents for
treatment of protozoan infections is a vital endeavor with great demand in the
future.
Author(s) Details
Dr. Ronald Bartzatt
University of Nebraska,
Durham Science Center, 6001 Dodge Street, Omaha, Nebraska 68182, USA.
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