OTAVAchemicals Receptor-Based Approach to Design Target-Focused Libraries

Our company offers unique docking-based target-focused libraries. They are produced based on computational estimation of compounds’ interaction with one specific member in a protein family (sharpfocusing approach). Each library contains about 2,000 compounds selected from OTAVAchemicals collection of 500,000 in-stock compounds.

 

WHY OTAVAchemicals FOCUSED LIBRARIES?

Our proprietary method for receptor-based virtual screening of compounds includes powerful combination of drug-likeness filtering, molecular docking, re-scoring, key intermolecular hydrogen bond detection and,finally, visual inspection of ligand-receptor complexes. The main advantage of our focused libraries is that each compound in every library is finally selected manually:

  • using drug-likeness filtering, molecular docking, re-scoring and H-bond detection scientists initially reduce input library of half a million compounds to about 10,000 and then
  • a panel of our experts analyzes these compounds manually. They visually inspect about 10,000 ligand-receptor complexes for proper binding mode: hydrogen bonding, hydrophobic interactions as well as orientation of ligands in a binding site, and finally
  • look into the diversity of chemical scaffolds

It is demanding, but in this way we could insure that our customers will get the most promising candidate molecules for their specific tasks. Our approach works and our scientists already found a number of new kinase inhibitors with high activity and selectivity [1-4].

Fig. 1. Design flowchart of receptor-based focused libraries.

 

OTAVAchemicals UNIQUE CALCULATION ALGORITHM

To prepare these focused libraries, our experts have implemented a number of crucial improvements of a calculation algorithm which include calculation of atom charges as well as unique force field and scoring functions [5-7]. Taking into account key electrostatic interactions between molecules, we developed a specific chargedefinition algorithm which uses Kirchhoff method for electronegativity relaxation. This allowed us to treat electrostatic terms more accurately. To achieve reasonable acceleration in entropy loss measurement, we applied harmonic approximation for integration of configuration space of a ligand-receptor complex. Scoring function also requires co-crystallized water environment to be efficient. Therefore, we developed new method to calculate and predict binding of water molecules to the formed complex on sub-second timescale.

 

MOLECULAR DYNAMICS

As part of our Contract Research projects we also utilize MD simulation for limited number of complexes to study their binding modes in more detail. This approach allows us to make right decisions on further structural optimization of lead molecules.

 

REFERENCES (PUBLISHED BY OTAVAchemicals SCIENTISTS)

  1. Gryshchenko AA, Tarnavskiy SS, Levchenko KV, Bdzhola VG, Volynets GP, Golub AG, Ruban TP, Vygranenko KV, Lukash LL, Yarmoluk SM. Design, synthesis and biological evaluation of 5-amino-4-(1H-benzoimidazol-2-yl)-phenyl-1,2-dihydro-pyrrol-3-ones as inhibitors of protein kinase FGFR1. Bioorg Med Chem 2016, 24 (9), 2053-2059.
  2. Gudzera OI, Golub AG, Bdzhola VG, Volynets GP, Lukashov SS, Kovalenko OP, Kriklivyi IA, Yaremchuk AD, Starosyla SA, Yarmoluk SM, Tukalo MA. Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase. Bioorg Med Chem, 2016, 24 (5), 1023-1031.
  3. Starosyla SA, Volynets GP, Lukashov SS, Gorbatiuk OB, Golub AG, Bdzhola VG, Yarmoluk SM. Identification of apoptosis signal-regulating kinase 1 (ASK1) inhibitors among the derivatives of benzothiazol-2-yl-3-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one. Bioorg Med Chem, 2015, 23 (10), 2489-2497.
  4. Guerra B, Bischoff N, Bdzhola VG, Yarmoluk SM, Issinger OG, Golub AG, Niefind K. A note of caution on the role of halogen bonds for protein kinase/inhibitor recognition suggested by high- and low-salt CK2α complex structures. ACS Chem Biol, 2015, 10 (7), 1654-1660.
  5. Hunnigan K, Kulkarni SS, Bdzhola VG, Golub AG, Yarmoluk SM, Talele TT. Identification of novel PARP-1 inhibitors by structure-based virtual screening. Bioorg Med Chem Lett, 2013, 23, 5790-5794.
  6. Golub AG, Gurukumar KR, Basu A, Bdzhola VG, Bilokin Y, Yarmoluk SM, Lee J-C, Talele TT, Nichols DB, Kaushik-Basu N. Discovery of New Scaffolds for Rational Design of HCV NS5B Polymerase Inhibitors. Eur J Med Chem, 2012, 58, 258-264.
  7. Sapelkin et al. Application of 4-substituted 3-carboxyquinolines as protein kinase CK2 inhibitors. Pat. UА68984 А, C07D215/00, 2004-08-16.
  8. Prykhod'ko et al. Application of 4,5,6,7-tetrahalogeno-1,3-isoindolinediones as protein kinase CK2 inhibitors. Pat. UA69165 А, С07D215/00, 2004-08-16.
  9. Yakovenko et al. Kirchhoff atomic charges fitted to multipole moments: implementation for a virtual screening system. Journal of Computational Chemistry, 2008, 29 (8), 1332-1343.
  10. Yakovenko et al. The new method of distribution integrals evaluations for high throughput virtual screening. Ukrainica Bioorganica Acta, 2007, 5 (1), 52-62.
 
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