Pharmacophore and FTrees Abhik Seal Indiana University Bloomington November 16
Pharmacophore• IUPAC Definition: “An ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response“ H Aromatic HBA R HBD• In drug design, the term pharmacophore‘ refers to a set of features that is common to a series of active molecules• Hydrogen-bond donors and acceptors, positively and negatively charged groups, and hydrophobic regions are typical features We will refer to such features as pharmacophoric groups
Bioisosteres• Bioisosteres, which are atoms, functional groups or molecules with similar physical and chemical properties such that they produce generally similar biological properties .• A chemical group can be mimicked by a similar group with similar biological activity –another example of similarity for example in a. Size b. Shape (bond angles, hybridization) c. Electronic distribution (Polarizability, inductive effects, charge, dipoles) e. Lipid solubilityf. pKag. Chemical reactivity (including likelihood of metabolism)h. Hydrogen bonding capacity
3D Pharmacophores• A three-dimensional pharmacophore specifies the spatial relation-ships between the groups• Expressed as distance ranges,angles and planes• A commonly used 3D pharmacophore for antihistamines contains two aromatic rings and a tertiary nitrogen Tak Taken from Laak etal. J.Med Chem1995,38(17)
Example of ACE inhibitors..• Angiotension-converting enzyme (ACE), which is involved in regulating blood pressure . Interacts with an Arg residue of enzyme H bonds to a hydrogen-bond donor in enzyme Pharmacophore a zinc-binding group Captopril 4 points 5 distances
Detection of Pharmacophores: SBP and LBPA pharmacophore software detects the elements which is responsible for pharmacophoricproperties.For Ligand based pharmacophore pharmacophoric points.a) Aromacity detection or ring detectionb) HBD point is normaly bsaed on topological information .Every atom is checked for the following conditions:• Only nitrogen or oxygen atoms;• Formal charge is not negative;• At least 1 attached hydrogen atom.c) The generation of hydrogen bond acceptor points needs to fulfill four conditions:• Only nitrogen or oxygen atoms;• Formal charge not positive;• At least one available lone pair;• Atom is ‘accessible’. d) For the generation of charge center pharmacophore points, the formal charges on the atomsof the molecule are used. Atoms with a positive formal charge will correspond with a positivecharge center pharmacophore point
Structure based pharmacophoreDistance Constraints represent the relation between two points, one located on the ligand side, oneon the macromolecular side.The following table shows LigandScouts default distance constraint settings:Aromatic interaction with 3.5 - 5.5 Åpositive ionizableAromatic interaction with ring 2.8 - 4.5 Å(parallel)Aromatic interaction with ring 2.8 - 4.5 Å(orthogonal)H-Bond interaction 2.2 - 3.8 ÅHydrophobic interaction 1.0 - 5.9 ÅIron binding location 1.3 - 3.5 ÅMagnesium binding location 1.5 - 3.8 ÅNegative ionizable interaction 1.5 - 5.5 ÅPositive ionizable interaction 1.5 - 5.5 Åwith negative ionizablePositive ionizable interaction 1.0 - 10.0 Åwith aromatic ringZinc binding location 1.0 - 4.0 Å
Merging and aligning Pharmacophores• The quantification of the similarity between two pharmacophores can be computed from the overlap volume of the Gaussian volumes of the respective pharmacophores.• The procedure to compute the volume overlap between two pharmacophores is implemented in two steps. a) a list of all feasible combinations of overlapping pharmacophore points is generated. b) then corresponding features are aligned with each other using an optimization algorithm. The combination of features that gives the maximal volume overlap is retained to give the matching score • Each pharmacophore point is modeled as a 3-dimensional spherical Gaussian volume represented by its center (coordinate) and spread (a). The definition of the Gaussian pexp m r volume is given as follows: 2 Vp dr Vp being the Gaussian volume, p being normalization constant to scale the total volume to a level that is in relation to atomic volumes, m being the center of the Gaussian, and r being the distance variable that is integrated. that defines the volume of the point in space. is chosen inverse proportional to the square root of the radius.
3D database searching 6-8Å 2-3Å 3D 4 - 7.2 Å Database• The first stage employs some form of rapid screen to eliminate molecules that could not match the query. For eg: One way to develop is to encode information of the distances in the form of Bit strings. Where each bit position would correspond to a range of distance between specific pair of atoms. For initialization at first the bit string is set to 0 at all bit positions and then for each molecular conformation the bit string positions are set to 1. Then the final Encoded bit string is searched against a database to look for similar molecules.• The second stage uses a graph-matching procedure to identify those structures that do truly match the query. Eg : Clique detection.
Clique Detection methods• When many pharmacophoric groups are present in the molecule it may be very difficult to identify all possible combinations of the functional groups• Clique is defined as a maximal completely connected subgraph• Clique detection algorithms can be applied to a set of pre-calculated conformations of the molecules• Cliques are based upon the graph-theoretical approach to molecular structure . similar pattern
Descriptors• Molecular descriptors are used for retrieval of compounds and also for clustering and and property prediction.• Most descriptors use today are in linear format such as the properties are stored in the form of a vector.• The alignment free approach of comparison is extremely fast but it has disadvantages i.e the relative arragnment of funtional groups on the molecular surface cannot be determined and its weakly described in linear descriptors.• On the other hand 3D model can be itself considered as descriptor and they are aligned in 3D space , but its is difficult due to conformational flexibility and it might miss the right alignment.
Feature Trees• Mixed 2D and 3D ligand-based approach• Alignment based but conformation independent descriptor.• A feature tree represents a molecule by a tree such that the tree should capture the major Building blocks of the molecule in addition tothe overall alignment.• In this way lead hopping between Chemical classes with compounds Sharing the same wanted biological activity is supported.
Ftrees• The nodes of the Ftrees represents the fragments of the molecule.• Each atom of the molecule is associated with with at least one node.• Two nodes which have atoms in common or which contain atoms connected in the molecular graph are connected.• The feature tree nodes are marked with labels describing the shape and chemical properrties of the bulding block. Taken from Rarey etal JCADD 1998
Descriptors in Ftrees• The shape descriptors has two components i.e the number of atoms and the approximated vander wall’s volume.• Chemical features is used to describe the interaction pattern the Building Ftree can form The FlexX interaction pattern is used which is represented .• All the features taken are additive Taken from Rarey etal JCADD 1998
Comparison algorithm• The comparison algorithm of two feature trees is based on matching the trees i.e a subtree of one feature to that of another.• a,b is the number of atoms of the compared fragments.i th entry describes the ability of a Fragment to form interaction of type i.• On comparing the full Ftree we just add all the features and apply the eq. such a Comparison is level -o• For comparing feature Trees split search and match Search algorithms are used .These algorithms match based on the topology I,e it maintains the topology.
Scaffold hopping example• The Ftrees can identify actives from decoys Of H4R receptor proteins. Score:0.839 Score:0.875 Score 0.835