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Article-pharm modeling

Molecular Docking of Cathepsin L Inhibitors in the Binding Site of Papain

Supporting Info

Mary Pat Beavers*^†^‡, Michael C. Myers^†^§, Parag P. Shah^†^‡, Jeremy E. Purvis^‡, Scott L. Diamond^†^‡, Barry S. Cooperman^†^§, Donna M. Huryn^†^§ and Amos B. Smith, III^†^§

Penn Center for Molecular Discovery, Institute for Medicine and Engineering, and Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104

J. Chem. Inf. Model., 2008, 48 (7), pp 1464–1472

DOI: 10.1021/ci800085c

Publication Date (Web): July 4, 2008

* Corresponding author phone: 215-573-7311; fax: 215-573-7227; e-mail: marypat@seas.upenn.edu.

†

Penn Center for Molecular Discovery.

‡

Institute for Medicine and Engineering.

Department of Chemistry.

Abstract

The papain/CLIK-148 coordinate system was employed as a model to study the interactions of a nonpeptide thiocarbazate inhibitor of cathepsin L (1). This small molecule inhibitor, a thiol ester containing a diacyl hydrazine functionality and one stereogenic center, was most active as the S-enantiomer, with an IC₅₀ of 56 nM; the R-enantiomer (2) displayed only weak activity (33 μM). Correspondingly, molecular docking studies with Extra Precision Glide revealed a correlation between score and biological activity for the two thiocarbazate enantiomers when a structural water was preserved. The molecular interactions between 1 and papain were very similar to the interactions observed for CLIK-148 (3a and 3b) with papain, especially with regard to the hydrogen-bonding and lipophilic interactions of the ligands with conserved residues in the catalytic binding site. Subsequent docking of virtual compounds in the binding site led to the identification of a more potent inhibitor (5), with an IC₅₀ of 7.0 nM. These docking studies revealed that favorable energy scores and correspondingly favorable biological activities could be realized when the virtual compound design included occupation of the S2, S3, and S1′ subsites by hydrophobic and aromatic functionalities of the ligand, and at least three hydrogen bonding contacts between the ligand and the conserved binding site residues of the protein.

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