molecular docking Flashcards
when to use molecular docking
when 3D structure is known (its a structure based method)
what is docking
in silico fitting of a drug into a target binding site
what does in silico mean
computer/virtual
considerations of molecular docking
size shape, binding interactions of both drug and binding site
how is docking carried out and what is it used for
-carried out using molecular modelling programs manually or automatically
-useful for virtual screening of compound libraries to identify structures that are likely to bind to a target binding site
what are docking algorithms required to do and what does that depend on
dock molecules and score how effectively they bind, depends on how well they fit and how many binding interactions are formed, compromise between speed and accuracy (lower score=less effective)
what is the receptor/host
receiving molecule
what is the ligand/guest
complementary partner that binds to the receptor/host
what is docking
computational simulation of a candidate ligand binding to a receptor
what is binding mode
orientation of ligand relative to receptor and conformation of ligand and receptor when bound to each other
what is a pose
candidate binding mode
what is scoring
process of evaluating a particular pose by counting the number of favourable intermolecular interactions
what is ranking
process of clarifying which ligands are most likely to interact favourably to a particular receptor based on the predicted free energy of binding
name the 3 methods of docking
rigid target and rigid ligand (simplest, quickest, acceptable if active conformation of ligand is known)
rigid target flexible ligand (more complex but feasible)
flexible target and flexible ligand (very complex, expensive on computer time, not practical)
how to find a target binding site
-obtain 3D structure of protein by xray crystallography
-identify binding site by using known active sites/structural analysis/software
-identify amino acids lining the binding site
-define molecular surface of binding site
-molecular surface is defined based on VDW radius of atoms showing accessible areas for ligands
two types of rigid docking
by shape and by matching Hydrogen bonding groups
what are Connolly surfaces in docking by shape
a VDW surface accessible to a solvent molecule, when a probe rolls over a VDW surface
-has convex and concave regions
describe the convex and concave regions on a connolly surface
convex= (hills) areas where probe makes contact with VDW surface
concave= (dips down) re entrants representing how far the probe access space between atoms lining the binding stie, common for ligand to bind here)
describe the docking program when rigid docking by shape
overlay is carried out by systemic matching operation for distance matching, what things are measured
what happens after measuring
rigid docking by shape complementarity, shape of ligand matched to available space in binding site, binding site defined by dots, space available defined by spheres
-distance between ligand atoms measured, distance between centres of pseudo atoms measured
-identifies sets of ligand atoms that can match up with the set of pseudo atoms (matching operation) and carries out docking process, docking repeated for other possible pairs, can have multiple solutions
rigid docking by shape can have several solutions found, what is done when multiple are found
filtering process, removes any solutions with steric clashes between unmatched ligand atoms and binding stie surface
what are steric clashes
overlap of atoms between protein and ligand that would prevent the two from binding
VDW interactions attract atoms weakly but better when closer together, what happens when they get too close
strong repel
what is ideal when docking by shape
ligand fills up most space available
describe rigid docking by matching hydrogen bonding groups
-hydrogen bonding groups in ligand and binding stie gets matched up
-complementary H bonding groups must be correctly separated and must have correct orientation with respect to each other
