Molecular Docking of Chiral Drug Enantiomers With Different Bioactivities.

Chirality has an important role in the drug design because enantiomers may exhibit different bioactivity when interacting with macromolecules of a living organism. In our previous work, based on the analysis of a set of 100 chiral drugs, a relationship was established between the sign of chirality of enantiomers and their bioactivity. To understand the reasons for the observed patterns of chiral specificity of drug enantiomers, the interaction of 10 enantiomeric pairs of chiral drugs with the corresponding target proteins has been considered using molecular docking and further postprocessing by quantum chemistry methods.

Design, Synthesis, and Evaluation of New Hybrid Derivatives of 5,6-Dihydro-4-pyrrolo[3,2,1-]quinolin-2(1)-one as Potential Dual Inhibitors of Blood Coagulation Factors Xa and XIa.

Cardiovascular diseases caused by blood coagulation system disorders are one of the leading causes of morbidity and mortality in the world. Research shows that blood clotting factors are involved in these thrombotic processes. Among them, factor Xa occupies a key position in the blood coagulation cascade.

New Hybrid Tetrahydropyrrolo[3,2,1-]quinolin-1-ylidene-2-thioxothiazolidin-4-ones as New Inhibitors of Factor Xa and Factor XIa: Design, Synthesis, and In Silico and Experimental Evaluation.

Despite extensive research in the field of thrombotic diseases, the prevention of blood clots remains an important area of study. Therefore, the development of new anticoagulant drugs with better therapeutic profiles and fewer side effects to combat thrombus formation is still needed. Herein, we report the synthesis and evaluation of novel pyrroloquinolinedione-based rhodanine derivatives, which were chosen from 24 developed derivatives by docking as potential molecules to inhibit the clotting factors Xa and XIa.

Docking Paradigm in Drug Design.

Docking is in demand for the rational computer aided structure based drug design. A review of docking methods and programs is presented. Different types of docking programs are described.

Advances in Docking.

Background: Design of small molecules which are able to bind to the protein responsible for a disease is the key step of the entire process of the new medicine discovery. Atomistic computer modeling can significantly improve effectiveness of such design. The accurate calculation of the free energy of binding a small molecule (a ligand) to the target protein is the most important problem of such modeling.

New generation of docking programs: Supercomputer validation of force fields and quantum-chemical methods for docking.

Discovery of new inhibitors of the protein associated with a given disease is the initial and most important stage of the whole process of the rational development of new pharmaceutical substances. New inhibitors block the active site of the target protein and the disease is cured. Computer-aided molecular modeling can considerably increase effectiveness of new inhibitors development.

Evaluation of the novel algorithm of flexible ligand docking with moveable target-protein atoms.

We present the novel docking algorithm based on the Tensor Train decomposition and the TT-Cross global optimization. The algorithm is applied to the docking problem with flexible ligand and moveable protein atoms. The energy of the protein-ligand complex is calculated in the frame of the MMFF94 force field in vacuum.

Evaluation of Docking Target Functions by the Comprehensive Investigation of Protein-Ligand Energy Minima.

The adequate choice of the docking target function impacts the accuracy of the ligand positioning as well as the accuracy of the protein-ligand binding energy calculation. To evaluate a docking target function we compared positions of its minima with the experimentally known pose of the ligand in the protein active site. We evaluated five docking target functions based on either the MMFF94 force field or the PM7 quantum-chemical method with or without implicit solvent models: PCM, COSMO, and SGB.

Application of Molecular Modeling to Development of New Factor Xa Inhibitors.

In consequence of the key role of factor Xa in the clotting cascade and absence of its activity in the processes that do not affect coagulation, this protein is an attractive target for development of new blood coagulation inhibitors. Factor Xa is more effective and convenient target for creation of anticoagulants than thrombin, inhibition of which may cause some side effects. This study is aimed at finding new inhibitors of factor Xa by molecular computer modeling including docking SOL and postdocking optimization DISCORE programs.

Application of the docking program SOL for CSAR benchmark.

This paper is devoted to results obtained by the docking program SOL and the post-processing program DISCORE at the CSAR benchmark. SOL and DISCORE programs are described. SOL is the original docking program developed on the basis of the genetic algorithm, MMFF94 force field, rigid protein, precalculated energy grid including desolvation in the frame of simplified GB model, vdW, and electrostatic interactions and taking into account the ligand internal strain energy.