gCOMBINE: A graphical user interface to perform structure‐based comparative binding energy (COMBINE) analysis on a set of ligand‐receptor complexes

Abstract

We present gCOMBINE, a Java-written graphical user interface (GUI) for performing comparative binding energy (COMBINE) analysis (Ortiz et al. J Med Chem 1995; 38:2681-2691) on a set of ligand-receptor complexeswith the aim of deriving highly informative quantitative structure-activity relationships. The essence of the method is to decompose the ligand-receptor interaction energies into a series of terms, explore the origins of the variance within the set using Principal Component Analysis, and then assign weights to selected ligandresidue interactions using partial least squares analysis to correlate with the experimental activities or binding affinities. The GUI allows plenty of interactivity and provides multiple plots representing the energy descriptors entering the analysis, scores, loadings, experimental versus predicted regression lines, and the evolution of parameterssuch as r(2) (correlation coefficient), q(2) (cross-validated r(2)), and prediction errors as the number of extracted latent variables increases. Other representative features include the implementation of a sigmoidal dielectric function for electrostatic energy calculations, alternative cross-validation procedures (leave-N-out and random groups), drawing of confidence ellipses, and the possibility to carry out several additional tasks such as optional truncation of positive interaction energy values and generation of ready-to-use PDB files containing information related to the importance for activity of individual protein residues. This information can be displayed and color-coded using a standard molecular graphics program such as PyMOL. It is expected that this user-friendly tool will expand the applicability of the COMBINE analysis method and encourage more groups to use it in their drug design research programs.

Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE)

“…The gCOMBINE program [38] (provided by A. Morreale) was used to decompose the interaction energy between the inhibitor and the protein in each minimized complex. That is, this program was used to calculate the Lennard-Jones and electrostatic interactions between the inhibitor and each protein residue.…”

“…The COMBINE method, first developed by A. R. Ortiz in 1995 [30], has been widely applied in the field of drug design [31-37]. In 2010, Gil-Redondo et al developed gCOMBINE [38], a Java graphical user interface (GUI), to perform COMBINE analyses, providing a convenient tool for academic researchers. The key idea of COMBINE analysis is that a simple expression describing the differences in binding affinity of a series of related ligand-receptor complexes can be derived by using multivariate statistics to correlate experimental data on binding affinities with components of the ligand-receptor interaction energy computed from energy-minimized 3D structures.…”

Fast and accurate determination of the relative binding affinities of small compounds to HIV-1 protease using non-equilibrium work

“…Several computational methods for predicting the ligand binding affinity have been available. These computational approaches can be classified in three main group: the fastest prediction can be achieved using the quantitative structure‐activity relationship (QSAR) approach, and the molecular docking simulations; the approximate estimation methods such as the linear interaction energy (LIE), and molecular mechanics‐Poisson‐Boltzmann surface area (MM‐PBSA) . The MM‐PBSA, and the LIE methods have been applied because they provide a good balance between CPU computing consumption and the accuracy desired.…”

Structural basis for the development of SARS 3CL protease inhibitors from a peptide mimic to an aza‐decaline scaffold

“…The parametrization for the gCOMBINE was performed on the tLEaP module in AMBERTOOL14 program suits. The PDB files of the receptor protease were cleaned by pdb4amber .…”

“…The COMparative BINding Energy (COMBINE) method developed by Ortiz is a powerful pipeline for the decomposition of the ligand–receptor interaction energies into a series of terms, extracting latent variables (LV) for the explanation of the interactions and then, assigning weights to selected ligand–residue interactions using multivariate statistics and partial least square (PLS) analysis to correlate with a set of ligand–receptor complexes data on the experimental activities or binding affinities. Gil‐Redondo and colleagues developed gCOMBINE, which is a user‐friendly graphical interface, to perform the analysis with defined input files and sophisticated result presentations. Since the ligand‐induced structural alternation is taken into account, ligand–receptor interactions can be better understood by chemometrical analysis.…”