Computational studies on protein-ligand docking

This thesis describes the development and refinement of a number of techniques for molecular docking and ligand database screening, as well as the application of these techniques to predict the structures of several protein-ligand complexes and to discover novel ligands of an important receptor protein. Global energy optimisation by Monte-Carlo minimisation in internal co-ordinates was used to predict bound conformations of eight protein-ligand complexes. Experimental X-ray crystallography structures became available after the predictions were made. Comparison with the X-ray structures showed that the docking procedure placed 30 to 70% of the ligand molecule correctly within 1.5A from the native structure. The discrimination potential for identification of high-affinity ligands was derived and optimised using a large set of available protein-ligand complex structures. A fast boundary-element solvation electrostatic calculation algorithm was implemented to evaluate the solvation component of the discrimination potential. An accelerated docking procedure utilising pre-calculated grid potentials was developed and tested. For 23 receptors and 63 ligands extracted from X-ray structures, the docking and discrimination protocol was capable of correct identification of the majority of native receptor-ligand couples. 51 complexes with known structures were predicted. 35 predictions were within 3A from the native structure, giving correct overall positioning of the ligand, and 26 were within 2A, reproducing a detailed picture of the receptor-ligand interaction. Docking and ligand discrimination potential evaluation was applied to screen the database of more than 150000 commercially available compounds for binding to the fibroblast growth factor receptor tyrosine kinase, the protein implicated in several pathological cell growth aberrations. As expected, a number of compounds selected by the screening protocol turned out to be known inhibitors of the tyrosine kinases. 49 putative novel ligands identified by the screening protocol were experimentally tested and five compounds have shown inhibition of phosphorylation activity of the kinase. These compounds can be used as leads for further drug development

Ligand-biased ensemble receptor docking (LigBEnD): a hybrid ligand/receptor structure-based approach.

Ligand docking to flexible protein molecules can be efficiently carried out through ensemble docking to multiple protein conformations, either from experimental X-ray structures or from in silico simulations. The success of ensemble docking often requires the careful selection of complementary protein conformations, through docking and scoring of known co-crystallized ligands. False positives, in which a ligand in a wrong pose achieves a better docking score than that of native pose, arise as additional protein conformations are added. In the current study, we developed a new ligand-biased ensemble receptor docking method and composite scoring function which combine the use of ligand-based atomic property field (APF) method with receptor structure-based docking. This method helps us to correctly dock 30 out of 36 ligands presented by the D3R docking challenge. For the six mis-docked ligands, the cognate receptor structures prove to be too different from the 40 available experimental Pocketome conformations used for docking and could be identified only by receptor sampling beyond experimentally explored conformational subspace

BioSuper: A web tool for the superimposition of biomolecules and assemblies with rotational symmetry

Background Most of the proteins in the Protein Data Bank (PDB) are oligomeric complexes consisting of two or more subunits that associate by rotational or helical symmetries. Despite the myriad of superimposition tools in the literature, we could not find any able to account for rotational symmetry and display the graphical results in the web browser. Results BioSuper is a free web server that superimposes and calculates the root mean square deviation (RMSD) of protein complexes displaying rotational symmetry. To the best of our knowledge, BioSuper is the first tool of its kind that provides immediate interactive visualization of the graphical results in the browser, biomolecule generator capabilities, different levels of atom selection, sequence-dependent and structure-based superimposition types, and is the only web tool that takes into account the equivalence of atoms in side chains displaying symmetry ambiguity. BioSuper uses ICM program functionality as a core for the superimpositions and displays the results as text, HTML tables and 3D interactive molecular objects that can be visualized in the browser or in Android and iOS platforms with a free plugin. Conclusions BioSuper is a fast and functional tool that allows for pairwise superimposition of proteins and assemblies displaying rotational symmetry. The web server was created after our own frustration when attempting to superimpose flexible oligomers. We strongly believe that its user-friendly and functional design will be of great interest for structural and computational biologists who need to superimpose oligomeric proteins (or any protein). BioSuper web server is freely available to all users at http://ablab.ucsd.edu/BioSuper webcite

Acquired heart defects: Clinical picture, diagnosis

In acquired heart defects, they are defined as the occurrence of an irreversible violation in its structure, that leads to a complete loss of its function, changes in intracardiac hemodynamics, as well as change in intracardiac hemodynamics, as a result of which there is an overload of the corresponding parts of the heart, hypertrophy and dilatation of the chambers and circulatory disorders throughout the body. The main causes of valvular heart disease formation: the hereditary connective tissue disorder (mitral valve prolapse, leading to severe mitral insuficience) and other connection tissue disorders (mitral valve prolapse leads to severa mitral insufficiency) • infectious or rheumatic endocarditis

Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites

A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB

PIER: protein interface recognition for structural proteomics

Abstract Recent advances in structural proteomics call for development of fast and reliable automatic methods for prediction of functional surfaces of proteins with known three-dimensional structure, including binding sites for known and unknown protein partners as well as oligomerization interfaces. Despite significant progress the problem is still far from being solved. Most existing methods rely, at least partially, on evolutionary information from multiple sequence alignments (MSA) projected on protein surface. The common drawback of such methods is their limited applicability to the proteins with a sparse set of sequential homologs, as well as inability to detect interfaces in evolutionary variable regions. In this study, we developed an improved method for predicting interfaces from a single protein structure, that is based on local statistical properties of the protein surface derived at the level of atomic groups. It was also demonstrated that the evolutionary conservation signal only marginally influenced the overall prediction performance on a diverse benchmark; moreover, for certain classes of proteins, using this signal actually resulted in a deteriorated prediction. The proposed Protein IntErface Recognition method (PIER) yielded improved performance as compared to several alignment-free or alignment-dependent predictions. PIER achieved the overall precision of 60% at the recall threshold of 50% at the residue level on a benchmark of 490 homodimeric, 62 heterodimeric and 196 transient interfaces. For 696 of 748 proteins (93%) the binding patch residues were successfully detected with precision exceeding 25% at 50% recall; for 524 proteins (70%) the corresponding precision was above 50%. The calculation only took seconds for an average 300-residue protein. The accuracy, efficiency, and dependence on structure alone make PIER a suitable tool for automated high-throughput annotation of protein structures emerging from structural proteomics projects

Diagnosis and principles of treatment of congenital heart defects

Congenital heart disease (CHD) is a fairly common pathology of the cardiovascular system, which is the main cause of death in children in the first year of life. The frequency of CHD is 30% of all malformations. The number of HPUs in our country is increasing by 3-4% annually. In Russia, every 125 newborns have one with congenital heart disease or blood vessels. At the same time, in one out of 200 newborns, congenital malformations of the heart and blood vessels are of a combined nature, that is, they occur in various combinations, and, therefore, have a more severe clinical course. The main function of the cardiovascular system is the delivery and provision of oxygen and nutrients to all organs and tissues, as well as the reverse transportation of carbon dioxide and metabolic products. With each contraction, the heart normally ejects 70-120 ml of blood (stroke volume). The minute volume of the heart (the amount of blood ejected by the left ventricle in 1 minute) is normally 5500-7000 ml / min. And it largely depends on the height and weight of the person