LigFit module in Cerius2 4 scoring functions used

-LigScore, -PLP, -PMF, and LUDI

CScore module in SYBYL -FScore, -G-Score, -D-Score, and -ChemScore AutoDock

-DrugScore and -X-Score

Conformational sampling and scoring are divided into two consecutive steps exhaustive conformational sampling is performed by using the Auto Dock program To generate large no of conformations for each ligand ( preferred because it cover the entire conformational space as much as possible) Then after each scoring function as above mentioned is applied This scoring functions were evaluated depending on their reproducibility with experimental conformation 6 best scoring function found where PLP, F-Score, LigScore, DrugScore,

LUDI, and X-Score (better than Autodock) ( Success rate 66 76 % on basis of < 2 RMSD)
Reproducibility of result above 0.5 correlation coefficient were found in X-Score, PLP, DrugScore, and G-Score X-Score & DrugScore are best in constructing descriptive funnel shaped energy surface for protein-ligand complexation

Todays docking programs, this sampling procedure is based on either genetic algorithm, Monte Carlo simulation, simulated annealing, distance geometry, or other miscellaneous methods. According to article first part thats conformation generation is not more important that scoring function algorithm selection Scoring function (or energy function) is used to evaluate the fitness between the protein and the ligand. Approach for selecting scoring function for protein-ligand interaction is broadly devided into 3 group 1. force field methods 2. empirical scoring functions, 3. knowledge-based potentials Especially useful when one has an immediate interest in seeking active compounds for a particular target through virtual database screening Any software uses a combination of docking and scoring algorithm which may give promising result Commercial software's uses a combination of docking and scoring function but if the outcome fails its difficult to blame that is it due docking algorithm or scoring algorithm or both. Even when all of the scoring functions are tested in the context of one docking program, there is still another problem: the docking program is typically run with a default set of parameters, which does not guarantee an adequate sampling of possible docked conformations.

Importance of Conformational sampling

Autodock is preferred for generating group of docked confirmation for each ligand Autodock uses genetic algorithm (GA) for conf. sampling

Factors considered for initial setup

Parameter
Resolution of Protein Mol. Wt. of ligand Rotatable bonds Dissociation constant (-log Kd or Ki ) Ligand binding Protein Protein ligand complex Protein Ligand Metal ion Organic and Inorganic cofactors Water molecules

Factors considered
< 2.5 Ao 100 900 0-20 1.5-10.5 Must be non-covalent Must be splitted Save on .PDB format Save in .mol2 format If present in active cavity dont delete Must be deleted Deleted (except imp reported in literature)

Hydrogen bonds Atom type & bond type

Charge assignment

Must be added to both protein and ligand Inspect and correct

Protein - AMBER united atom charge Ligand MMFF94 charge