title: An Ab Initio Method for Designing Multi-Target Specific Pharmacophores using Complementary Interaction Field of Aspartic Proteases.
abstract: For past few decades, key objectives of rational drug discovery have been the designing of specific and selective ligands for target proteins. Infectious diseases like malaria are continuously becoming resistant to traditional medicines, which inculcates need for new approaches to design inhibitors for antimalarial targets. A novel method for ab initio designing of multi target specific pharmacophores using the interaction field maps of active sites of multiple proteins has been developed to design 'specificity' pharmacophores for aspartic proteases. The molecular interaction field grid maps of active sites of aspartic proteases (plasmepsin II & IV from Plasmodium falciparum, plasmepsin from Plasmodium vivax, pepsin & cathepsin D from human) are calculated and common pharmacophoric features for favourable binding spots in active sites are extracted in the form of cliques of graphs using inductive logic programming (ILP). The two pharmacophore ensembles are constructed from largest common cliques by imposing size of receptor active site (L) and domain-specific receptor-ligand information (S). The overlap of chemical space between two ensembles and the results of virtual screening of inhibitor database with known activities show that this method can design efficient pharmacophores with no prior ligand information.
authors.affiliation: School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India phone/fax:9971287771.
authors.forename: Rama
authors.initials: R
authors.lastname: Kaalia
authors.affiliation: School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India phone/fax:9971287771.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Indraprastha Institute of Information Technology, New Delhi-110020, India.|Current address: Department of Computer Science, BITS-Pilani, Goa-403726, India.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Srinivasan
authors.affiliation: School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi-110067, India phone/fax:9971287771. indira0654@gmail.com.
authors.forename: Indira
authors.initials: I
authors.lastname: Ghosh
mesh_terms: D057055:Aspartic Acid Proteases / Q000037:antagonists & inhibitors / Q000737:chemistry; D020134:Catalytic Domain; D004341:Drug Evaluation / Q000379:methods; D006801:Humans; D010963:Plasmodium falciparum / Q000201:enzymology*; D010966:Plasmodium vivax / Q000201:enzymology*; D011480:Protease Inhibitors / Q000737:chemistry*; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
chemical_list: D011480:Protease Inhibitors; D015800:Protozoan Proteins; D057055:Aspartic Acid Proteases
keywords: Clique detection; Inductive logic program; Molecular interaction field; Molecular modeling; Pharmacophore model