The Semiempirical Quantum Mechanical Scoring Function for In-Silico Drug Design

Jindřich Fanfrlík, Martin Lepšík, Jan Řezáč, Michal Kolář, Adam Pecina, Dana Nachtigallová and  Pavel Hobza

Institute of Organic Chemistry and Biochemistry and Gilead Science and IOCB Research Center, Academy of Sciences of the Czech Republic, Flemingovo nam. 2, 166 10 Prague 6, Czech Republic, tel.: (+420) 220 410318,


This poster introduces the quantum mechanics (QM)-based computer-aided drug design, especially using semiempirical QM (SQM) methods. Computer-aided drug design aims to reduce the cost of the drug development and also to bring deeper insight into the inhibitor binding to its target. Binding free energy (ΔGbº) between protein (P) and a ligand (L), which is related to the dissociation constant (Ki) of the P-L complex, is expected to be proportional to the ligand potency.

Free energy estimators are mostly referred to as scoring functions in the drug-design community. The score stands for the binding free energy or for some generalized quantity describing the ligand potency. Previously, we designed a scoring function based on the semiempirical quantum mechanical (SQM) PM6-DH2X method and applied it to several types of P-L complexes, namely the HIV-1 protease (PR),1 cyclin-dependent kinase 2 (CDK2),2 casein kinase 2 (CK2),3 adenosine kinase,4 aldose reductase,5 serine racemase6 binding to series of inhibitors. The score consist of the interaction energy, the desolvation free energy, the change of the conformational 'free' energies of the protein and ligand upon binding and the entropy change. The most accurate up-to-date methods are used for the respective terms thus offering a balanced and reliable scoring function. Let us emphasize that each of the terms has a clear physical meaning and that these terms are not adjusted/weighted by any means (fitting parameters) to the experimental data. Construction of the scoring function from the physically meaningful terms is a significant feature since it allows us to gain a deeper insight into the nature of the P-L binding.


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