Application of Molecular Modeling to Development of New Factor Xa Inhibitors

Computational and Structural Biotechnology Journal

Zheltkov

Oferkin³

et al. 2017

Self Cite

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. The grid of precalculated energy potentials of probe ligand atoms in the field of the target protein atoms is not used. The energy of the protein-ligand complex for any given configuration is computed directly with the MMFF94 force field without any fitting parameters. The conformation space of the system coordinates is formed by translations and rotations of the ligand as a whole, by the ligand torsions and also by Cartesian coordinates of the selected target protein atoms. Mobility of protein and ligand atoms is taken into account in the docking process simultaneously and equally. The algorithm is realized in the novel parallel docking SOL-P program and results of its performance for a set of 30 protein-ligand complexes are presented. Dependence of the docking positioning accuracy is investigated as a function of parameters of the docking algorithm and the number of protein moveable atoms. It is shown that mobility of the protein atoms improves docking positioning accuracy. The SOL-P program is able to perform docking of a flexible ligand into the active site of the target protein with several dozens of protein moveable atoms: the native crystallized ligand pose is correctly found as the global energy minimum in the search space with 157 dimensions using 4700 CPU ∗ h at the Lomonosov supercomputer.

Section: Methodsmentioning

confidence: 99%

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

Computational and Structural Biotechnology Journal

Zheltkov

Oferkin³

et al. 2017

Self Cite

“…Современные тенденции в области разработки препаратов, связанных с фактором свертывания Ха, характеризуются двумя направлениями. С одной стороны, растет число случаев идентификации новых классов прямых ингибиторов фактора Ха, причем чаще всего с использованием методов молекулярного моделирования [52][53][54][55][56]. Примеры некоторых новых ингибиторов, разработанных с помощью компьютерного моделирования, приведены в таблице 2.…”

Section: прямые ингибиторы ключевых факторов свертыванияunclassified

Blood coagulation in the 21st century: existing knowledge, current strategies for treatment and perspective

Подоплелова

Voprosy gematologii/onkologii i immunopatologii v pediatrii

Tashchilova

et al. 2020

Disorders in the blood coagulation system are the leading cause of death and disability in the modern world. So the search for new drugs that can prevent pathological thrombosis, while not affecting normal hemostasis, becomes more relevant than ever. Recent studies has been a revolution in the understanding of the principles of work and the regulation of blood coagulation. In addition, new, more effective approaches to drug development have now appeared. For example computer simulation methods that can significantly reduce the time and resources spent on the search for new candidate molecules. In the review, the blood clotting system, the molekular mechanisms of thrombosis, the role of blood coagulation factors Xa and XIa, and the urgency of developing new inhibitors of these targets are shown, and the most interesting inhibitors of factors Xa and XIa are presented.

“…Для примера кратко опишем организацию работы и алгоритм докинга, реализованные в программе SOL [4,[10][11][12], которые эффективно применяли для разработки ингибиторов факторов свертываемости крови -тромбина [38] и фактора Xa [39,40]. Сетка потенциалов строится с помощью модуля SOLGRID на основе силового поля MMFF94.…”

Section: докинг и другие методы компьютерного моделирования лекарствеunclassified

Modern methods for the development of new drugs that affect the hemostatic system

Voprosy gematologii/onkologii i immunopatologii v pediatrii

Kutov

Tashchilova

et al. 2019

The blood coagulation system plays an important role in health and disease. It is a complex network of proteolytic reactions that is activated during injuries and controls the formation of a fibrin clot. Although new components and reactions have not been discovered for thirty years, during this time there has been a revolution in understanding of how this system works and what enzymes are the optimal targets for the therapy. At the same time, new methods of drug development, first of all, computer docking, which are ideally suited for the discovery of inhibitors of blood clotting enzymes, have appeared. In this review, an attempt has been made to correlate the lines of development of new ideas about the mechanisms of coagulation, new methods of searching for drugs and their combination, thanks to which now there are more and more potentially interesting molecules that can change the face of the anticoagulant therapy in the near future. In the review, molecular modeling methods, primarily docking, which are increasingly used at the initial stage of developing new drugs, the role of docking at the initial stage of developing new inhibitors are briefly considered and the structure of the active centers of factors Xa and XIa, which determines their interaction with inhibitors, are discussed in detail.