Rational in silico design of aptamers for organophosphates based on the example of paraoxon

Area of Science:

• Biotechnology and Pharmaceutical Sciences
• Computational Chemistry and Molecular Modeling

Background:

• Organophosphate (OP) poisoning is a significant global health concern, necessitating effective detoxification strategies.
• Aptamers, particularly DNA or RNA aptamers, offer a promising approach for capturing OP toxins in the bloodstream.

Purpose of the Study:

• To develop and validate a rational in silico design strategy for creating high-affinity aptamers targeting organophosphates.
• To utilize paraoxon as a model OP compound for aptamer design and evaluation.

Main Methods:

• Construction of a 3D model for a known OP-binding aptamer sequence.
• Molecular docking and molecular dynamics (MD) simulations to identify the paraoxon binding site.
• Mutagenesis of binding site nucleotides, free binding energy calculations (MD trajectories, MM-PBSA), and comparative binding energy analysis against acetylcholinesterase (AChE).

Main Results:

• Identification of two novel aptamer sequences with enhanced binding efficiency for paraoxon.
• Computational analysis revealed that the designed aptamers bind paraoxon more strongly than AChE.
• Detailed analysis of paraoxon-nucleotide interactions within the aptamer binding sites was performed.

Conclusions:

• The in silico approach enables the rational design of effective aptamers for organophosphate detoxification.
• The developed aptamers demonstrate superior binding affinity for paraoxon compared to the natural target AChE.
• This study highlights the potential for improving in silico aptamer selection methodologies.