An efficient in silico screening method based on the protein-compound affinity matrix and its application to the design of a focused library for cytochrome P450 (CYP) ligands.

Yoshifumi Fukunishi; Shinichi Hojo; Haruki Nakamura

doi:10.1021/ci600334u

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An efficient in silico screening method based on the protein-compound affinity matrix and its application to the design of a focused library for cytochrome P450 (CYP) ligands.

Yoshifumi Fukunishi·Shinichi Hojo·Haruki Nakamura

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Abstract

A new method has been developed to design a focused library based on available active compounds using protein-compound docking simulations. This method was applied to the design of a focused library for cytochrome P450 (CYP) ligands, not only to distinguish CYP ligands from other compounds but also to identify the putative ligands for a particular CYP. Principal component analysis (PCA) was applied to the protein-compound affinity matrix, which was obtained by thorough docking calculations between a large set of protein pockets and chemical compounds. Each compound was depicted as a point in the PCA space. Compounds that were close to the known active compounds were selected as candidate hit compounds. A machine-learning technique optimized the docking scores of the protein-compound affinity matrix to maximize the database enrichment of the known active compounds, providing an optimized focused library.

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Artificial Intelligence Binding Sites Chemistry, Pharmaceutical Combinatorial Chemistry Techniques Cytochrome P-450 Enzyme System Drug Evaluation, Preclinical Drug Industry Humans Ligands Models, Chemical Models, Statistical Polymorphism, Genetic Principal Component Analysis Proteins Quantitative Structure-Activity Relationship Technology, Pharmaceutical Journal Article Research Support, Non-U.S. Gov't

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Yoshifumi Fukunishi, Shinichi Hojo, Haruki Nakamura. An efficient in silico screening method based on the protein-compound affinity matrix and its application to the design of a focused library for cytochrome P450 (CYP) ligands.. https://doi.org/10.1021/ci600334u

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