engleski

Evaluation of scoring functions use in case of acetylcholinesterase inhibitors

Introduction: Molecular modelling tools are recognised as helpful in a drug design and medicinal chemistry. Proper evaluation of receptor-ligand interaction is main goal in drug design and development. Next step will be a prediction of receptor-ligand interaction with respect to affinity, required for a ligand structure optimization. Recognition of key interactions is beneficial for developing selective and high affinity ligands. Scoring functions are introduced for this purpose. They are developed by correlating interactions from numerous crystal structures of various different receptor-ligand complexes with matching inhibition constant. Results: Here we evaluated several high affinity acetylcholinesterase inhibitors using scoring functions to determine correlation between reported inhibition constant for following inhibitor complexes PDB ID: 1E66, 1EVE, 1H22, 1H23, 1U65, 1ZGB and 1ZGC, and score values derived from scoring functions. We used following scoring functions available in Accelrys DiscoveryStudio software: PLP1, PLP2 [1], PMF, PMF04 [2], Jain [3], LigScore1 and LigScore2 [4]. Deviation between inhibition constants was 10% while deviation between matching scores were from 12 to 40%. Conclusions: Scoring function LigScore2 and PLP2 evaluated well acetylcholinesterase-inhibitor complexes with lowest score deviation. Although LigScore2 predicted logarithmic value of affinity in two cases (1H23 and 1ZGC), some disagreement was noticed due to 25% lower value of predicted affinities. References: 1. Gehlhaar DK, et al. (1995) Chem. Biol. 2, 317-24. 2. Muegge I, (2006) J. Med. Chem. 49(20), 5895-5902. 3. Jain AN, (1996) J. Comput.-Aided Mol. Design 10, 427-440. 4. Krammer A, et al. (2005) J. Mol. Graph. Model. 23, 395-407.

molecular modelling; receptor-ligand interactions; scoring functions

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