engleski

Evaluation of scoring functions use in the case of acetylcholinesterase inhibitors

Molecular modelling tools are recognised as helpful in drug design and medicinal chemistry. Proper evaluation of receptor-ligand interaction is one of the main goals in drug design and development. Predicting receptor-ligand interaction with respect to binding affinity represents the next step, as this is what is required to optimise the ligand structure. Recognition of key interactions is essential for developing selective and high affinity ligands and scoring functions have been introduced to this end. They are developed by correlating interactions from numerous crystal structures of various different receptor-ligand complexes with the matching inhibition constant. In this study, we evaluated several high affinity acetylcholinesterase inhibitors using scoring functions to determine the correlation between the reported inhibition constants for the following inhibitor complexes PDB ID: 1E66, 1EVE, 1H22, 1H23, 1U65, 1ZGB, and 1ZGC, and score values derived from scoring functions. We used the following scoring functions available in Accelrys Discovery Studio software: PLP1, PLP2[1], PMF, PMF04[2], Jain[3], LigScore1, and LigScore2[4]. Deviation between inhibition constants was 10 % while deviation between matching scores ranged between 12 and 40 %. Scoring functions LigScore2 and PLP2 provided a sound evaluation of acetylcholinesterase-inhibitor complexes with the lowest relative score deviation. Although LigScore2 predicted a logarithmic value of affinity in two cases (1H23 and 1ZGC), some disagreement was noticed due to 20 % lower value of predicted affinities in average. [1] Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DR, Fogel LJ, Freer ST (1995) Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem Biol 2:317–324. [2] Muegge I (2006) PMF Scoring Revisited. J Med Chem 49:5895-5902. [3] Jain AN (1996) Scoring noncovalent protein-ligand interactions: A continuous differentiable function tuned to compute binding affinities. J Comput–Aided Mol Design 10:427–440. [4] Krammer A, Kirchhoff PD, Jiang X, Venkatachalam CM, Waldman M (2005) LigScore: a novel scoring function for predicting binding affinities. J Mol Graph Model 23:395-407.

Acetylcholinesterase; Scoring function; Receptor; Ligand

http://www.irb.hr/eng/content/download/8902/200751/file/Book-of-Abstracts_crosb2012.pdf