The document outlines the process of drug designing for tuberculosis, covering various aspects such as target identification, validation, structure retrieval, and final model development using computational methods. It details the steps involved in creating a prospective drug, including ligand binding affinity analysis and biosafety considerations. Additionally, it provides references to software and resources used throughout the drug design process.

1. Vikas Sinhmar
2K9/BT/8028

2. Various sectors of IBI:

3. CONTENTS:
 Drug designing
 Tuberculosis - an overview
 Target Identification
 Target Validation
 Structure Retrieval
 Structure Validation
 Final Model
 Active Site Identification
 Lead Identification

4.  Lead Insertion In Active Site
 Development Of Lead In Active Site
 Docking
 Proposal to Final Molecule
 Bibliography

5. Drug Designing:
Drug designing is a process used in biopharmaceutical
industry to discover and develop new drug
compounds.
 Variety of computational methods are used to identify
novel compounds ,design compounds for selectivity
and safety.
Structure-based drug design, ligand-based drug
design , homology based methods are used depending
on how much information is available about drug
targets and potential drug compounds.

6. Tuberculosis:
 Tuberculosis is a infectious disease caused by various
strains of mycobacteria ,usually mycobacterium
tuberculosis.
 Tuberculosis typically attacks the lungs , but can also
affect other parts of the body.
 It is spread through the air when the people who have
an active TB infection cough , sneeze or otherwise
transmit their saliva through air.

7. Chest X-ray:infetion in lungs

8. Symptoms of active TB:
 Chronic cough
 Fever
 Night Sweats
 Blood-tinged sputum
 Unusual weight loss

9. TARGET IDENTIFICATION:
 A “DRUG TARGET” is a key molecule involved in a
particular metabolic and signaling pathway that is
specific to disease condition and pathology , or to the
infectivity or survival of a microbial pathogen.
 Some steps are involved:
 search for all the molecules ,enzymes and proteins
involved in disease.
Found all these sequence on
:http//www.ncbi.nlm.nih.gov
Got the sequences in FASTA format

10. TARGET VALIDATION:
Perform the protein blast for all the genes/proteins
w.r.t homosapiens . Select the least matching molecule
in human and again perform the BLAST now in
protein(sub-heading) category. As the query sequence
matched best with Rv0554 , so we selected our target
molecule and its structure can be obtained from
RCSB(The Research Collaboratory for Structural
Bioinformatics) protein data bank.

11. BLAST against homo-sapiens

12. Structure of Rv0554 on spdbv:

13. STRUCTURE RETRIVAL:
Homology modeling using
software modeller
3 files of different format were
made of extension .atm, .ali, .py
Final five models were
obtained.

14. STRUCTURE VALIDATION:
 Five best models were ready .
 We viewed these models in SPDB viewer software to
select the best model .we analyzed all models in the
structure analysis and verification server.
 All these five models were prochecked.
 Upload pdb file then procheck.
 Pdb file with least warning selected.

16. FINAL MODEL/STRUCTURE VALIDATION:

17. LEAD IDENIFICATION:
 By using the software ligsite buliding pocket sites
were created for the resulting molecule.

19. DEVELOPMENT OF LEAD TO ACTIVE SITE:
 Software named LIGBUILDER used for development
of lead to active site.
 Best hex file(pocket file made by software hex) and file
with extracted heat atoms .
 Pocket command pocket(space)pocket.index
grow
Process

20. DOCKING:
The basic assumption underlying in-silico(SBDD) based
Drug designing is that a good ligand molecule bind
tightly to its target. Hence ,these ligand molecules are
analyzed for their binding affinity . The molecule
having maximum negative value of free energy and
minimum root mean square value is selected.
This will be done by a software AUTODOCK.

22. Ligand before and after docking

23. 3-D structure in SPDB viewer

24. BIOSAFETY:MOLSOFT LLC

25. PROPOSAL FOR FINAL MOLECULE:
 PASS(Prediction of activity spectra for substance), this
online tool predict over 3500 kinds of biological
activity including pharmacological effect, mechanism
of action , toxic and adverse effects, interaction with
metabolic enzymes and transporters , influence on
gene expression etc.
 Ligand possesses all the properties predicted by
Lipinski’s rule of five and ability to solublised in the
body & the drug likeness is 0.31 , which indicates , it is
very much similar to know drug , hence supporting it
to be as prospective drug.

26. BIBLOGRAPHY:
 SITE ACCESSED
*RCSB PDB-www.pdb.org/
*LIGSITEcsc – projects.biotec.tu-dresden.de/pocket/
*NCBI www.ncbi.nlm.nih.gov/
*PubMed.home-NCBI
www.ncbi.nlm.nih.gov>NCBI>literature
*SAVes-NIH MBI Laboratory for Structural Genomics
And Proteomics
*nihserver.mbi.ucla.edu/SAVES/Server

27. SOTWARES USED:
*Modellar9v8
*Procheck
*Ligsite
*Auto dock tools 1.5.4
*Python 2.5
*Ligbuilderv1.2
*Hex6.3
*Spdb-viewer
*Marvin-sketch
*OpenBabel GUI
*Mol Inspiration
*Molsoft LLC
*PASS (Prediction of Activity Spectra for Substances)