An evaluation of the precision of computational methods used in drug development initiatives.

Abstract

Computational approaches are commonly employed to expedite and provide decision-making for the drug development process. Drug development programs that involve targets without known crystal structures can be quite challenging. In many cases, a viable approach is to generate reliable homology models using the amino acid sequence of the target. This is followed by a series of validation steps, druggable pocket detection, and then moving forward with lead identification and validation. This study commenced by conducting an initial benchmark exercise using a series of computationally designed sequences for steroid-binding proteins. By conducting an unbiased comparison with the released X-ray crystal structures, the homology models that were generated demonstrated reliable outcomes. The aligned homology models showed a root mean square deviation (RMSD) of less than 0.6 Å when compared to the corresponding X-ray structures. Three different methods were used to detect the druggable cavities for comparison, and the identified pockets closely resembled those of the crystal structures. The achievement of near-native pose prediction was made possible by utilizing the comprehensive binding energy function that characterizes the interaction between each pose and the neighboring residues. In order to address the issue of limited correlation between entropy and internal energy in docking, an alternative was devised by incorporating entropy as a post-docking optimization step to enhance the accuracy of ligand binding affinity predictions and improve the overall quality of the results.