3rd Users' Conference of IT4Innovations

On the Performance of Semiempirical Quantum Mechanics-Based Scoring Functions for Virtual Screening Applications

Not scheduled

3h

atrium (IT4Innovations)

Poster Poster session Conference Dinner & Poster Session

Speakers

Saltuk Mustafa Eyrilmez (Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Regional Centre of Advanced Technologies and Materials, Palacký University) Cemal Köprülüoğlu (Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Regional Centre of Advanced Technologies and Materials, Palacký University)

Description

Abstract

Drugs exert their action mainly by noncovalent binding to their biological targets, thus modulating or inhibiting their functions. Accurate investigation of noncovalent interactions is critically dependent on the use of computationally demanding quantum mechanics (QM). In our laboratory, we have developed[1] corrected semiempirical QM (SQM) methods for accurate calculation of protein-ligand interactions. We have ascertained that such an approach outperforms all classically used scoring functions (SF) in ligand ranking[2] as well as identifying the ligand native pose in cognate docking[3, 4]. One of our main aim was to develop and validate a general protocol, which will enable us to make SQM methods affordable for virtual screening of compound libraries for target protein binding. We are introducing a newly improved SF, based on the SQM PM6-D3H4X method combined with the conductor-like screening implicit solvent model (COSMO). The SQM/COSMO, Amber/GB and nine widely used SFs have been evaluated in terms of ranking power on the HSP90 protein with 72 biologically active compounds and 4875 structurally similar decoys. Among conventional SFs, the highest early and overall enrichment measured by EF1 and AUC% obtained using single-scoring-function ranking has been found for Glide–SP and Gold–ASP SFs, respectively (6, 72% and 3, 76%). The performance of other standard SFs has not been satisfactory, mostly even decreasing below random values. The SQM/COSMO SF, where P–L structures were optimised at the advanced Amber level, has resulted in a dramatic enrichment increase (47, 98%), almost reaching the best possible ROC curve. Notice that no specific parameters have been introduced in either PM6-D3H4X or COSMO methods. Current findings could be of high importance for structure-based drug design and related applications[5].

References

1. Řezáč, J.; Hobza, P. J. Chem. Theory Comput. 2012, 8, 141–151.
2. Pecina, A.; Brynda, J.; Vrzal, L.; Gnanasekaran, R.; Hořejší, M.; Eyrilmez, S., M.; Řezáč, J.; Lepšík, M.; Řezáčová, P.; Hobza, P.; Majer, P.; Veverka V.; Fanfrlik, J. ChemPhysChem 2018, 19, 873-879.
3. Pecina, A.; Meier, R.; Fanfrlik, J.; Lepšík, M.; Řezáč, J.; Hobza, P.; Baldauf, C. Chem. Commun. 2016, 52, 3312-331511.
4. Ajani, H.; Pecina, A.;Eyrilmez, S., M.; Fanfrlik, J.; Haldar, S.; Řezáč, J.; Hobza, P.; Lepsik, M. ACS Omega 2017, 2, 4022-4029
5. Eyrilmez, S., M.; Köprülüoğlu, C.; Řezáč, J.; Hobza, P. ChemPhysChem 2019,
   https://doi.org/10.1002/cphc.201900628

Acknowledgements

This work was part of the Research Project RVO: 61388963 of the Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences. We acknowledge the support from the European Regional Development Fund; OP RDE; Project: ‘Chemical Biology for Drugging Undruggable Targets (ChemBioDrug)’ (No. CZ.02.1.01/ 0.0/0.0/ 16_019/ 0000729). This work was also supported by the Ministry of Education, Youth and Sports from the Large Infrastructures for Research, Experimental Development and Innovations project ‘IT4Innovations National Supercomputing Center – LM2015070’.