Close intramolecular sulfur-oxygen contacts: modified force field parameters for improved conformation generation

Area of Science:

• Computational chemistry
• Molecular modeling
• Drug discovery

Background:

• Small molecule conformations are crucial for molecular interactions and drug efficacy.
• Existing molecular mechanics force fields (e.g., MMFFs, OPLS_2005) inadequately model specific sulfur-oxygen (S···O) interactions.
• These limitations lead to inaccurate geometries and energetics in simulations.

Purpose of the Study:

• To develop modified OPLS_2005 force field parameters for accurate S···O interaction modeling.
• To improve the prediction of small molecule conformations found in the Cambridge Structural Database (CSD).
• To enhance the accuracy of geometry minimizations and conformational searches.

Main Methods:

• Analysis of 130 small molecules from the CSD with close intramolecular S···O distances.
• Modification of OPLS_2005 force field parameters, including torsional parameters and van der Waals (vdW) terms.
• Attenuation of electrostatic interactions for specific atom pairs.
• Validation through geometry minimizations and conformational searches.

Main Results:

• Modified OPLS_2005 parameters achieved 58% accuracy in conformational searches, compared to 25% (MMFFs) and 37% (OPLS_2005).
• Improved parameters successfully generated conformations for axitinib, enabling correct repacking into observed polymorphic structures.
• The new parameters address inadequacies in existing force fields for S···O interactions.

Conclusions:

• The developed OPLS_2005 parameters significantly enhance the accuracy of small molecule conformational prediction.
• These improved parameters are valuable for medicinal chemistry, materials science, and drug design.
• The approach offers a pathway to refine other molecular mechanics force fields for specific interactions.