1. A SEMINAR ON DESIGN OF
LIGANDS FOR KNOWN
RECEPTORS
DEPARTMENT OF PHARMACEUTICAL CHEMISTRY
MCOPS
SUBMITTED TO SUBMITTED BY
Dr Suvarna G. kinni Shikha Tyagi
Asst. professor 100602017

2. CONTENTS
INTRODUCTION
SITE IDENTIFICATION
SITE CHARACTERISATION
• HYDROGEN BONDING AND OTHER GROUPS
• ELECTROSTATIC AND HYDROPHOBIC FIELD
DESIGN OF LIGANDS
• VISUALLY ASSISTED DESIGN
• 3-D DATABASE
• DE NOVO DESIGN
CALCULATION OF AFFINITY

3. INTRODUCTION
LIGAND
A ligand (from the Latin ligandum, binding) is a substance that forms a
complex with a biomolecule to serve a biological purpose.

4. RECEPTOR:
A RECEPTOR IS A PROTEIN MOLECULE, EMBEDDED IN EITHER THE PLASMA
MEMBRANE OR THE CYTOPLASM OF A CELL, TO WHICH ONE OR MORE
SPECIFIC KINDS OF SIGNALING MOLECULES MAY ATTACH.
Cytoplasmic receptor
Membrane receptor

5. PHARMACOPHORE:
A PHARMACOPHORE IS AN ABSTRACT DESCRIPTION OF MOLECULAR
FEATURES WHICH ARE NECESSARY FOR MOLECULAR RECOGNITION OF A
LIGAND BY A BIOLOGICAL MACROMOLECULE.
THE IUPAC DEFINES A PHARMACOPHORE TO BE "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.

6. DESIGN OF LIGANDS TWO TYPES LIGAND BASED AND STRUCTURE BASED
STRUCTURE BASED LIGAND BASED

7. SITE IDENTIFICATION
 3-D STRUCTURE BY NMR AND X –RAY CRYSTALLOGRAPHY
 BUT IT DOES NOT GUARANTEE THE SITE OF ACTION BY LIGANDS
SOMETIMES CONFORMATIONAL CHANGES OCCURES DURING THE BINDING
WHICH ARE NOT REFLECTED IN 3-D STRUCTURE
FOR EXAMPLE : WHEN MVT-101 A ANTI HIV DRUG BINDS TO THE HIV
PROTEASE ENZYME CONFORMATIONAL CHANGES OCCURS
the two β-strand flaps have been folded in, to complete the active site of HIV
protease, the important interactions for recognition in this proteolytic system
NMR- NOE CAN HELP IN INDENTIFICATION OF SUCH CONFORMATIONAL CHANGES.

8. Figure 3.14. Ribbon diagram of HIV-1
protease in the absence of inhibitor (a) and
when bound to the
inhibitor MVT-10103). Diagrams based on
crystal structures as reported by Miller et al.
Ribbon diagram of HIV-1 protease in the absence of inhibitor (a) and when bound
to the inhibitor MVT-101.

9. DYNAMICS OF RECEPTORS
IT IS VERY IMPORTANT TO ANSWER SOME QUESTIONS
Q1 HOW STABLE IS THE ACTIVE SITE TO MODIFICATION IN THE LIGAND
????????:.
Q1 Is THERE ANY ALTERNATIVE BINDING SITE WHICH IS COMPETING WITH
THE BINDING SITE OF LIGAND.????????
FOR EXAMPLE-
DIFFICULTY IN INTERPRETATION OF BINDING SITE AS A RESULT OF LIGAND
MODIFICATION OCCURS WHEN AN ANALOG DESIGN IS BIND TO THE SPECIFIC
SITE ON HEMOGLOBIN .ACTUALLY THIS ANALOG FOUND A MORE
APROPREIATE SITE WITHIN THE PACKED SIDE CHAIN OF THE PROTEIN
MOLECULE .THIS EMPHASIZE THE DYNAMICS OF PROTEIN MOLECULE.
SOLUTION – 3-D STRUCTURE OF CAVITY AND POCKETS ASSIST THE
BINDING INTERACTION AND DESIGN OF NOVEL LIGANDS

11. HOW IT IS DONE????????????????
DOCKING
IT EXPLORE THE STERIC COMPLEMENTORY BETWEEN LIGANDS AND
RECEPTORS OF 3-D STRUCTURE USING THE MOLECULAR SURFACE OF
RECEPTORS
USING THE MOLECULAR SURFACE OF RECEPTORS VOLUMETRIC
APPOXIMATION OF SURFACE IS DONE.
 IN THIS METHOD SET OF SPHERE OF VARIOUS SIZES PACKED
MATHEMATICALLY WITHIN IN IT.
THE DISTANCE BETWEEN THE CENTERS SERVES AS THE A COMPACT
REPRESENTATION OF SHAPE OF CAVITY
 LIGANDS ALSO CHARACTERISED IN THE SAME WAY AND THE DISTANCE
MATRIX OF LIGAND AND THE RECEPTOR IS COMPARED
AND THE POTENTIAL LIGAND IS SELECTED

12. CHARACTERISATION SITE
ONCE THE SITE IS IDENTIFIED IT IS CHARACTERISED FOR VARIOUS
PARAMETERS AS DESCRIBED BELOW
1 HYDROGEN BONDING AND OTHER GROUPS
IN EVALUATING THE POTENTIAL LIGANDS IT IS NECESSORY TO HAVE
THE KNOWLEDGE OF OPTIMAL POSITIONS OF THE FUNCTIONAL
GROUPS
GRID- ALLOWS A PROBE ATOM OR GROUP TO EXPLORE RECEPTOR
SITE CAVITY ON A LATTICE OR A GRID WHILE ESTIMATING THE
ENTHALPY OF INTERACTION.
3-D CONTOUR MAP IS GENERATED FROM THE INTERACTION ENERGY
WHICH GIVES THE GRAPHICAL REPRESENTATION OF POSITION OF
FUNCTIOL GROUP AND HENCE THE HYDROGEN BONDING .

13. COMFA-COMPARATIVE MOLECULAR FIELD ANALYSIS
COMPUTE INTERACTION OF PROBE WITH MOLECULE AT EACH POINT
ACTIVITY IS DIRECTLY RELATED TO STRUCTURAL PROPERTIES OF SYSTEM
STEPS INVOLVED
HYPOTHESIZE MECHANISM FOR BINDING BY IDENTIFING STRUCTURE OF
BINDING SITE
FIND EQUILIBRIUM GEOMETRY
CONSTRUCT LATTICE OR GRID OF POINTS
COMPUTE INTERACTION OF PROBE WITH MOLECULE AT EACH POINT
APPLY PLS
PREDICT

15. DYLOMS-
ELIMINATE THE PROBLEM OF RESOLUTION BY GRID .
IT ORIENT THE FUNCTIONAL GROUP FOR OPTIMAL INTERACTION WITH
THE BINDING SITE AND GENERATE NOVEL STRUCTURE.
HOW???
MULTIPLE COPIES OF LIGANDS IS DISTRIBUTED AT THE BINDING SITE BY
SIMULATION AND THEIR RELATIVE DISTRIBUTION IS EXAMINED.
POPULATION OF LIGANDS IS CONCENTRATED ON OPTIMAL BINDING
SITE .
 LIGANDS ARE CONNECTED WITH THE MOST ENERGETICALLY FAVOURED
BINDING SITE (I.e THE C-C OVERLAP OF THE LIGAND WITH THE FRAGMENT
OF BINDING SITE)
NOVEL LIGANDS ARE DESIGNED

16. ELECTROSTATIC AND HYDROPHOBIC
INTERACTIONS
SURFACE DISPLAYS THE PROPERTIES LIKE HYDROPHOBICITY AND
ELECTROSTATIC FIELD
MOLECULAR SURFACES DISPLAYS MAY BE COLOR CODED TO DEPICT THE
VARIOUS PROPERTIES.
SURFACE CAN BE DISPLAYED BY DOTS OR CONTOURS.
CAVITY DISPLAY-THE LOCI OF THE FILLER ATOMS PACKING THE CAVITY IS
COMPUTED
OUTRMOST LAYER OF THE FILLER SOLID IS IDENTIFIED .
THIS SURFACE DISPLAYS THE INTERFACE BETWEEN BINDING SITE AND THE
LIGAND ELCTROSTATIC INTERACTION.

17. AT EACH POINT ELECTROSTATIC POTENTIAL IS CALCULATED
.
VALUES ARE ASSIGNED BY COLOR AND DISPLAYED
REGIONS OF ELECTROSTATIC COMPLEMENTARITY AND DISPARITY ARE DOCKED
A ROUGH APPROXIMATION OF COMPLEMENTARITY IS COMPUTED BY
MULTIPLYING THESE POTENTIAL TOGETHER
NEGATIVE PRODUCT FAVOURS BINDING AND THE POSITIVE UNFAVOURABLE FOR
BINDING
NOVEL LIGAND IS DESIGNED IN THIS WAY.

18. DESIGN OF LIGANDS
VISUALLY ASSISTED DESIGN
BY DIRECTLY EXAMINE THE LIGAND WE CAN SELECT THE REGIONS WHERE
MODIFICATIONS CAN BE MADE.
BUT THIS IS DIFFICULT FOR THE RECEPTOR –LIGAND GAP REGION THIS IS DONE BY THE
CAVITY DISPLAY
 INTHIS APPROACH THE NEAREST DISTANCE BETWEEN THE ATOMS IN THE GAP IS
CALCULATED THAT IS THE SURFACE TO SURFACE DISTANCE.
COLOR CODING IS DONE TO DISPLAY THIS .

19. 3-D DATABASES
CAMBRIDGE STRUCTURAL DATA BASES—90,000 STRUCTURE
BROOKHAVEN PROTEIN DATABANK –
CONTAINS THE CRYSTALS CO-ORDINATES OF PROTEINS AND THE OTHER
BIOMOLECULE
 THIS CONSIST OF LOW ENERGY CONFORMER THAT IS READILY ATTAINABLE IN
SOLUTION OR THE RECEPTORS
3-D DATABASE IS SEARCHED BY USING A QUERY FOR FRAGMENT THAT CONTAIN
THE PHARMACOPHORIC FUNCTIONAL GROUP.IN PROPER 3-D DIMENSIONAL
ORIENTATION.
USING FRAGNMENTS AS THE BUILDING BLOCKS COMPLETE NOVEL STRUCTURE
MAY BE GENERATED BY ASSEMBLY AND PRUNING

20. PHARMACOPHORE MATCHING ESTROGEN MOLECULE

21. CONCORD
 CHEMICAL ABSTRACTS ARE GENERATED BY USING THIS
7,00,000 ENTERIES
THIS IS NONCRYSTALLOGRAPHIC DATABASE
IT IS USED WHEN THE CRYSTAL STRUCTURE OF LIGNAD – RECEPTOR
COMPLEX IS KNOWN.AND ITS BINDING IS WELL UNDERSTOOD IN TERMS OF
FUNCTIONAL GROUP.IN SUCH CASE LIGANDS CAN BE GENERATED BY USING
THE SCAFFOLDS THAT POSITION THE PHARMACOPHORIC GROUP OR THEIR
ISOSTERS IN THE CORRECT 3-D ARRANGEMENT
MOLPAT
 IS THE FIRST PROTOTYPE TO SEARCH FOR MOLECULE THAT MATCH 3-D
PHARMACOPHORIC PATTERN.
IT PERFORMS ATOM BY ATOM SEARCH TO VERIFY COMPARABLE
INTERATOMIC DISTANCES BETWEEN THE PATTERN AND THE CANDIDATE.

22. CAVEAT
TO IDENTIFY THE CYCLIC STRUCTURES
ALLADIN,3-D SEARCH,MACCS-3-D
FOR MOLECULAR PROPERTIES LIKE ATOM TYPE ,BOND
ANGLE,TORSIONAL ANGLE,LIGAND RECEPTOR COMPLEMENTORY.
CHEM-X
 CONFORMATIONAL SEARCH
MDS
 FOR THE CONFORMATIONAL SEARCH ,BINDING ENERGY ,FORCE
FIELDS, 3 –D STRUCTURES.VARIOUS MODELS LIKE BALL –STICK MODEL
SPACE MODEL

23. SHAPE MATCHING ALGORITHM
Sheridan et al screened candidate compounds to select those whose volumes
would fit within the combined volumes of known active compounds.
BROMOPERIDOL
JG-365

24. FOUNDATION-
3-D DATABASE OF CHEMICAL STRUCTURE FOR A USER DEFINED QUERY
CONSISTING OF THE CO-ORDINATES OF ATOMS AND BOND
ALL POSSIBLE STRUCTURES THAT CONTAINS ANY COMBINATION OF A
USER DEFINED MINIMUM NUMBER OF MATCHING ATOM AND BONDS ARE
RETERIVED..
SPLICE- TRIMS THE MOLECULE FOUND FROM THE DATABASE TO FIT WITHIN
THE ACTIVE SITE AND LOGICALLLY COMBINE THEM BY OVERLAPPING BONDS
TO MAXIMIZE INTERACTION WITH THE SITE.

25. DE NOVO DESIGN
Drug discovery and development is a complex, lengthy process, and failure of a candidate
molecule can occur as a result of a combination of reasons, such as poor pharmacokinetics, lack o
efficacy, or toxicity.
De novo drug design involves searching an immense space of feasible, druglike molecules to
select those with the highest chances of becoming drugs using computational technology.
Traditionally, de novo design has focused on designing molecules satisfying a single
objective, such as similarity to a known ligand or an interaction score, and ignored the presence o
the multiple objectives required for druglike behavior.
Recently, methods have appeared in the literature that attempt to design molecules satisfying
multiple predefined objectives and thereby produce candidate solutions with a higher chance of
serving as viable drug leads
BR
ge
BRIDGE is based on geometric generation of possible cyclic compounds as scaffolds, of
given constraints derived from the types of chemistry the chemist is willing to consider. co
sc
gi
de
LUDI to construct ligands for active sites with an empirical scoring function
to evaluate their construction.

26. CALCULATION OF AFFINITY
CALCULATION OF BINDING AFFINITY BASED ON THE 3- D STRUCTURE
WILLIAM USED VANCOMYCIN-PEPTIDE COMPLEX TO CALCULATE BINDING AFFINITY
IN TERMS OF GIBBS FREE ENERGY

27. ∆G(Trans + rot) - free energy associated with translational and rotational freedom
of the ligand. This has an adverse effect on binding of 50-70 kJ/mol (12-17 kcallmol)
at room temperature for ligands of 100-300 Dalton, assuming complete loss of
relative translational and rotational freedom
∆Grotors -free energy associated with the number of rotational degrees of freedom
frozen. This is 5-6 kJ/mol (1.2-1.6 kcal/mol) per rotatable bond, assuming complete
loss of rotational freedom.
∆H c o n f o m- is the strain energy introduced by complex formation (deformation
in bond lengths, bond angles, torsional angles, etc
.
∑∆ Gi is the sum of interaction free energies between polar groups
∆Gvdw-ENERGY DERIVED FROM THE ENHANCED VANDERWAALS INTERACTIONS
∆GH- FREE ENERGY ATTRIBUTED TO HYDROPHOBIC INTERACTION

28. REFERENCES
BURGER'S “MEDICINAL CHEMISTRY AND DRUG DISCOVERY”, 5th
Edition,Vol-I,Page no-599-612
http://pubs.acs.org/doi/abs/10.1021/ci800308h
http://en.wikipedia.org/wiki/File:biocomputing and drug design.

29. THANkU