HINT 2.30 Manual: Chapter One

Introduction

What is HINT?

HINT is a software package that utilizes experimental solvent partitioning data as a basis for an empirical molecular interaction model. The program calculates empirical atom-based hydropathic parameters that, in a sense, encode all significant intermolecular and intramolecular non-covalent interactions implicated in drug binding or protein folding. HINT provides tools to estimate numerical binding constants and to visualize hydropathy and hydropathic interactions. The only user-provided input data to HINT are the molecular structures of the species. The hydrophobic atom constants are calculated using an adaptation of the fragment constant methods of Leo and Rekker. The partition constant, LogP, is a thermodynamic parameter that, because of its unprocessed and unbiased experimental nature, contains interaction information specific to the biological environment as well as solvent effects and entropy.

Two types of output data are generated by HINT: Tabular lists of specific atom-atom interactions quantitated by a micro-interaction constant and a variety of graphical maps that reveal (1) hydropathy, (2) hydropathic interactions, and (3) hydropathy of an unknown, inferred complementary species (e.g., to design a substrate to fit a known receptor).

Typical uses for HINT include:

Calculating an empirical hydropathic field in or around a protein or small molecule, and displaying contours to qualitatively visualize hydrophobic and polar regions of the molecules.
Calculating a predicted binding interaction constant that is the sum of all atom-atom interactions between two species.
Determining the effects of site-directed mutagenesis on substrate-binding or protein subunit-subunit interactions.
Calculating maps that allow visualization of interactions between drugs and receptors or within proteins.
Predicting the hydropathic structure of a "key", the ideal molecule to fit a known receptor ("lock") to design enzyme inhibitors, etc.
Calculation of LogP and hydropathic maps for use with conventional and 3D QSAR; in particular HINT provides a empirical hydropathic field to supplement the electrostatic and steric fields of SYBYL'S CoMFA.

Selected HINT References

Allosteric Modifiers of Hemoglobin. 2. Crystallographically Determined Binding Sites and Hydrophobic Binding/Interaction Analysis of Novel Hemoglobin Oxygen Effectors. F.C. Wireko, G.E. Kellogg, and D.J. Abraham, J. Med. Chem. 1991, 34, 758-767.
HINT - A New Method of Empirical Hydrophobic Field Calculation for CoMFA. G.E. Kellogg, S.F. Semus, and D.J. Abraham, J. Computer Aided Mol. Design 1991, 5, 545-552.
New Tools for Modeling and Understanding Hydrophobicity and Hydrophobic Interactions. G.E. Kellogg, G.S. Joshi, and D.J. Abraham, Med. Chem. Res. 1992, 1, 444-453.
KEY, LOCK, and LOCKSMITH. Complementary Hydrophobicity Map Predictions of Drug Structure from a Known Receptor/Receptor Structure from Known Drugs. G.E. Kellogg and D.J. Abraham, J. Mol. Graph. 1992, 10, 212-217.
Evaluating Docked Complexes with the HINT Exponential Function and Empirical Atomic Hydrophobicities. E.C. Meng, I.D. Kuntz, D.J. Abraham, and G.E. Kellogg, J. Computer Aided Mol. Design 1994, 8, 299-306.
All-Atom Models for the Non-Nucleoside Binding Site of HIV-1 Reverse Transcriptase Complexed with Inhibitors: A 3D QSAR Approach. R. Gussio, N. Pattabiraman, D.W. Zaharevitz, G.E. Kellogg, I.A. Topol, W.G. Rice, C.A. Schaeffer, J.W. Erickson, and S.K. Burt, J. Med. Chem. 1996, 39, 1645-1650.
Hydropathic Analysis of the Non-covalent Interactions between Molecular Subunits of Structurally Characterized Hemoglobins. D.J. Abraham, G.E. Kellogg, J. M. Holt, and G. K. Ackers, J. Mol. Biol. 1997, 272, 613-632.

Trademark Acknowledgements and Disclaimers

HINT is a copyrighted program of Virginia Commonwealth University and eduSoft, LC.

hint!® is a registered trademark of eduSoft, LC.

InsightII, Sketcher, DelPhi and Discover are copyrighted programs of Molecular Simulations, Inc.

Sybyl, CoMFA and the Molecular Spreadsheet are copyrighted programs of Tripos, Inc.

DOCK is a copyrighted program of The Regents, University of California (San Francisco).

IRIS and IRIX are trademarks of Silicon Graphics, Inc.

UNIX is a trademark of Bell Laboratories.