Lead Finder
Encyclopedia
Lead Finder software is a computational chemistry application for modeling protein-ligand interactions. Lead Finder can be used in molecular docking
studies and for the quantitative evaluation of ligand binding and biological activity. It is free for individual non-commercial academic users.
for simulating structure and binding affinity of protein-ligand complexes. The software combines automatic processing of protein structures, extra precision protein-ligand docking and calculation of free energy of ligand binding. Original docking algorithm provides a fast rate of calculations, which can be easily adjusted from more rapid (for virtual screening
applications) to slightly more slow and robust, while unique scoring function implemented in Lead-Finder provides unsurpassed accuracy of calculations.
Lead-Finder is intended to meet the requirements of computational and medicinal chemists involved in drug discovery
, pharmacologists and toxicologists involved in the evaluation of ADMET properties in silico, and biochemists and enzymologists working on modeling protein-ligand interactions, enzyme
specificity and rational enzyme design.
Efficiency of ligand docking and binding energy estimations achieved by Lead-Finder are due to docking algorithm and extra precision representation of protein-ligand interactions.
search, local optimization procedures, and a smart exploitation of the knowledge generated during the search run. Rational combination of different optimization strategies makes Lead Finder efficient in terms of coarse sampling of ligand's phase space and refinement of promising solution
s.
is based on a semi-empiric molecular mechanical
functional, which explicitly accounts for different types of molecular interactions. Individual energy contributions are scaled with empiric coefficients to fit particular purposes: accurate binding energy predictions, correct energy-ranking of docked ligand poses, correct rank-ordering of active and inactive compounds during virtual screening experiments. For these reasons three distinct types of scoring functions based on the same set of energy contributions but different sets of energy-scaling coefficients are used by Lead-Finder.
. A set of 407 protein-ligand complexes was used for current docking success rate measurements. This set of complexes was combined from test sets used in original benchmarking studies of such docking programs as: FlexX, Glide SP, Glide XP, Gold, LigandFit, MolDock, Surflex.
Molecular docking
In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex...
studies and for the quantitative evaluation of ligand binding and biological activity. It is free for individual non-commercial academic users.
About
Lead-Finder software is an integrated solutionSolution
In chemistry, a solution is a homogeneous mixture composed of only one phase. In such a mixture, a solute is dissolved in another substance, known as a solvent. The solvent does the dissolving.- Types of solutions :...
for simulating structure and binding affinity of protein-ligand complexes. The software combines automatic processing of protein structures, extra precision protein-ligand docking and calculation of free energy of ligand binding. Original docking algorithm provides a fast rate of calculations, which can be easily adjusted from more rapid (for virtual screening
Virtual screening
Virtual screening is a computational technique used in drug discovery research. By using computers, it deals with the quick search of large libraries of chemical structures in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor or...
applications) to slightly more slow and robust, while unique scoring function implemented in Lead-Finder provides unsurpassed accuracy of calculations.
Lead-Finder is intended to meet the requirements of computational and medicinal chemists involved in drug discovery
Drug discovery
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered or designed.In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery...
, pharmacologists and toxicologists involved in the evaluation of ADMET properties in silico, and biochemists and enzymologists working on modeling protein-ligand interactions, enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
specificity and rational enzyme design.
Efficiency of ligand docking and binding energy estimations achieved by Lead-Finder are due to docking algorithm and extra precision representation of protein-ligand interactions.
Docking algorithm
From mathematical point of view ligand docking represents a search for global minimum on the multidimensional surface describing the free energy of protein-ligand binding. With ligands having up to 15-20 degrees of freedom (freely rotatable bonds) and complex nature of energy surface, global optimum search represents generally unsolved scientific task. To tackle this computationally challenging problem Lead-Finder applies unique approach combining genetic algorithmGenetic algorithm
A genetic algorithm is a search heuristic that mimics the process of natural evolution. This heuristic is routinely used to generate useful solutions to optimization and search problems...
search, local optimization procedures, and a smart exploitation of the knowledge generated during the search run. Rational combination of different optimization strategies makes Lead Finder efficient in terms of coarse sampling of ligand's phase space and refinement of promising solution
Solution
In chemistry, a solution is a homogeneous mixture composed of only one phase. In such a mixture, a solute is dissolved in another substance, known as a solvent. The solvent does the dissolving.- Types of solutions :...
s.
Scoring function
Extra precise representation of protein-ligand interactions implemented in Lead-Finder scoring function is the second (in addition to docking algorithm) component of successful ligand docking. Lead-Finder scoring functionScoring functions for docking
In the fields of computational chemistry and molecular modelling, scoring functions are fast approximate mathematical methods used to predict the strength of the non-covalent interaction between two molecules after they have been docked...
is based on a semi-empiric molecular mechanical
Molecular mechanics
Molecular mechanics uses Newtonian mechanics to model molecular systems. The potential energy of all systems in molecular mechanics is calculated using force fields...
functional, which explicitly accounts for different types of molecular interactions. Individual energy contributions are scaled with empiric coefficients to fit particular purposes: accurate binding energy predictions, correct energy-ranking of docked ligand poses, correct rank-ordering of active and inactive compounds during virtual screening experiments. For these reasons three distinct types of scoring functions based on the same set of energy contributions but different sets of energy-scaling coefficients are used by Lead-Finder.
Docking success rate
Docking success rate was benchmarked as a percentage of correctly docked ligands (for which top-scored pose was within 2 Å RMSD from the reference ligand coordinates) for a set of protein-ligand complexes extracted from PDBProtein Data Bank
The Protein Data Bank is a repository for the 3-D structural data of large biological molecules, such as proteins and nucleic acids....
. A set of 407 protein-ligand complexes was used for current docking success rate measurements. This set of complexes was combined from test sets used in original benchmarking studies of such docking programs as: FlexX, Glide SP, Glide XP, Gold, LigandFit, MolDock, Surflex.