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IVGA3D: De Novo Ligand Design Using a Variable Sized Tree Representation

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Abstract:

Rational drug design is an important step towards effective patient care enabling lead molecule discovery in a relatively faster and inexpensive way. This article describes a variable string length genetic algorithm with domain specific operators for de novo ligand design. The algorithm first mines the active site of the given protein receptor whose geometry and chemical composition guides the ligand building. Active site mined by the algorithm is compared with two more established active sites detecting schemes to evaluate its efficiency. Various combinations from a suite of forty one fragments are mined to design the ligands. Bond stretching, angle bending, torsional terms, van der Waals and electrostatic interaction energy with distance dependent dielectric constant contribute are used to compute the internal energy of the ligand and the interaction energy of the ligand receptor complex. Forty one fragments are used to design the ligands. Experimental results are provided for HIV-1 Protease, HIV-1 Nef and Thrombin demonstrating the superiority of the proposed scheme vis-a-vis three other approaches. Comparison with known inhibitors also demonstrates the effectiveness of the proposed approach.





Keywords: (FDA); (RMSD); CASTP; Cambridge Structural Database; ConQuest; Decoding a Chromosome; Drug design; Elitism; Food and Drug Administration; HIV infection; HIV-1 Nef; HIV-1 Protease; IVGA3D; LEA3D; NMR spectroscopy; Non-bonding interactions; Protein Data Bank; Q-SiteFinder; QSAR; RNA polymerase; Rational drug design; SARS; Thrombin; X-ray crystallography; active site; building block hypothesis; calmodulin; chromosome; chrysin; de novo ligand design; genetic algorithms; hydrophobic amino acids; major histocompatibility complex; methionine; octapeptide drug; polar hydroxyl group; variable length genetic algorithm

Document Type: Research Article

Publication date: 2010-12-01

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  • Protein & Peptide Letters publishes short papers in all important aspects of protein and peptide research, including structural studies, recombinant expression, function, synthesis, enzymology, immunology, molecular modeling, drug design etc. Manuscripts must have a significant element of novelty, timeliness and urgency that merit rapid publication. Reports of crystallisation, and preliminary structure determinations of biologically important proteins are acceptable. Purely theoretical papers are also acceptable provided they provide new insight into the principles of protein/peptide structure and function.
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