Protein binding sites for drug design

Abstract

Drug development is a lengthy and challenging process that can be accelerated at early stages by new mathematical approaches and modern computers. To address this important issue, we are developing new mathematical solutions for the detection and characterization of protein binding sites that are important for new drug development. In this review, we present algorithms based on graph theory combined with molecular dynamics simulations that we have developed for studying biological target proteins to provide important data for optimizing the early stages of new drug development. A particular focus is the development of new protein binding site prediction algorithms (ProBiS) and new web tools for modeling pharmaceutically interesting molecules-ProBiS Tools (algorithm, database, web server), which have evolved into a full-fledged graphical tool for studying proteins in the proteome. ProBiS differs from other structural algorithms in that it can align proteins with different folds without prior knowledge of the binding sites. It allows detection of similar binding sites and can predict molecular ligands of various types of pharmaceutical interest that could be advanced to drugs to treat a disease, based on the entire Protein Data Bank (PDB) and AlphaFold database, including proteins not yet in the PDB. All ProBiS Tools are freely available to the academic community at http://insilab.org and https://probis.nih.gov.

Keywords: Prediction; ProBiS; Protein binding sites; Structural proteome.

Fig. 1

Binding site and different possible ligands on a protein

Fig. 2

A maximum clique problem. Maximum clique (red) is the largest fully connected subgraph within a graph

Fig. 3

Timeline of ProBiS Tools development

Fig. 4

ProBiS-Fold web server as an extension of ProBiS-Dock Database with AlphaFold DB

Fig. 5

ProBiS-Fold web server results page shows a 3D view of a predicted binding site (blue surface) for the SARS-CoV-2 spike protein (gray cartoon) on a human angiotensin-converting enzyme 2 (ACE2) protein model from the AlphaFold database (model confidence-colored cartoon). Binding site residues on ACE2 are CPK-colored sticks. The list of predicted ligands for this binding site is below the viewer. Links to all the different predicted binding sites (protein, compound, cofactor, glycan, metal ion, and peptide) for the ACE2 protein are on the left