7 Conclusion
Computer-aided drug design leads to many successful discoveries of structure-based
drugs. Combination of molecular and quantum mechanics finds potential use in
investigation of enzymatic mechanism. Protein–protein interactions are found to be
relevant in drug design. Due to the sequencing of the human genome, many therapeutic targets are now available for structure-based drug design. Advancement in
many aspects of crystallography and NMR methods has contributed to the
high-resolution structures of many protein–protein–ligand complexes. Since each
computational method in the field of SBDD has its own field of applicability,
drawbacks, and limitations, they should be used in combination to come out with
potential drugs. Since potential links exist between drugs and diseases, drug
repurposing creates faster way in the field of drug discovery. In the design of
protein–protein interaction inhibitors, the challenge is to discover druggable pockets
in the interfaces of proteins engaged in transient interactions. A thorough study of
successive compounds binding the same target assists in understanding structure–
activity relationships, binding modes, and conformational changes. As more and
more human protein structures are getting solved, structure-based drug design will
have more impact in the discovery of new drugs to combat various diseases as
structural biology is a major partner in drug development.
Acknowledgements The authors would like to thank Dr. C. Ramakrishnan, Postdoctoral Fellow,
Department of Biotechnology, Indian Institute of Technology Madras, Chennai, for his kind help
in the revising of the manuscript.
References
1. Quanta/InsightII/Cerius2. Molecular Simulations Inc., 9685 Scranton Road, San Diego, CA
92121-3752
2. Sybyl. Tripos, Inc., 1699 South Hanley Road, St. Louis, MO 63144-2913
3. CAChe. CAChe Scientific, Inc., P.O. Box 4003, Beaverton, OR 97076
4. MacroModel. Department of Chemistry, Columbia University, New York, NY 10032
5. Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C et al (1984) A new force field for
molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 106:765–
784
6. DeLano WL (2002) The PyMOL molecular graphics system. http://pymol.org
7. Rosenfeld R, Vajda S, DeLisi C (1995) Flexible docking and design. Annu Rev Biophys
Biomol Struct 24:677–700
8. Lybrand TP (1995) Ligand-protein docking and rational drug design. Curr Opin Struct Biol
5:224–228
9. Jones G, Willett P (1995) Docking smallmolecule ligands into active sites. Curr Opin
Biotechnol 6:652–656
10. Kuntz ID, Meng EC, Shoichet BK (1994) Structure-based molecular design. Acc Chem Res
27:117–123
11. Schoichet BK, Kuntz ID (1996) Predicting the structure of protein complexes: a step in the
right direction. Chem Biol 3:151–156
Structure-Based Drug Design…
295
Computer-aided drug design leads to many successful discoveries of structure-based
drugs. Combination of molecular and quantum mechanics finds potential use in
investigation of enzymatic mechanism. Protein–protein interactions are found to be
relevant in drug design. Due to the sequencing of the human genome, many therapeutic targets are now available for structure-based drug design. Advancement in
many aspects of crystallography and NMR methods has contributed to the
high-resolution structures of many protein–protein–ligand complexes. Since each
computational method in the field of SBDD has its own field of applicability,
drawbacks, and limitations, they should be used in combination to come out with
potential drugs. Since potential links exist between drugs and diseases, drug
repurposing creates faster way in the field of drug discovery. In the design of
protein–protein interaction inhibitors, the challenge is to discover druggable pockets
in the interfaces of proteins engaged in transient interactions. A thorough study of
successive compounds binding the same target assists in understanding structure–
activity relationships, binding modes, and conformational changes. As more and
more human protein structures are getting solved, structure-based drug design will
have more impact in the discovery of new drugs to combat various diseases as
structural biology is a major partner in drug development.
Acknowledgements The authors would like to thank Dr. C. Ramakrishnan, Postdoctoral Fellow,
Department of Biotechnology, Indian Institute of Technology Madras, Chennai, for his kind help
in the revising of the manuscript.
References
1. Quanta/InsightII/Cerius2. Molecular Simulations Inc., 9685 Scranton Road, San Diego, CA
92121-3752
2. Sybyl. Tripos, Inc., 1699 South Hanley Road, St. Louis, MO 63144-2913
3. CAChe. CAChe Scientific, Inc., P.O. Box 4003, Beaverton, OR 97076
4. MacroModel. Department of Chemistry, Columbia University, New York, NY 10032
5. Weiner SJ, Kollman PA, Case DA, Singh UC, Ghio C et al (1984) A new force field for
molecular mechanical simulation of nucleic acids and proteins. J Am Chem Soc 106:765–
784
6. DeLano WL (2002) The PyMOL molecular graphics system. http://pymol.org
7. Rosenfeld R, Vajda S, DeLisi C (1995) Flexible docking and design. Annu Rev Biophys
Biomol Struct 24:677–700
8. Lybrand TP (1995) Ligand-protein docking and rational drug design. Curr Opin Struct Biol
5:224–228
9. Jones G, Willett P (1995) Docking smallmolecule ligands into active sites. Curr Opin
Biotechnol 6:652–656
10. Kuntz ID, Meng EC, Shoichet BK (1994) Structure-based molecular design. Acc Chem Res
27:117–123
11. Schoichet BK, Kuntz ID (1996) Predicting the structure of protein complexes: a step in the
right direction. Chem Biol 3:151–156
Structure-Based Drug Design…
295