Protein Binding Site Analysis for Drug Discovery Using a Computational Fragment-Based Method

Abstract

One of the most powerful tools for designing drug molecules is an understanding of the target protein's binding site. Identifying key amino acids and understanding the electronic, steric, and solvation properties of the site enables the design of potent ligands. Of equal importance for the success of a drug discovery program is the evaluation of binding site druggability. Determining, a priori, if a particular binding site has the appropriate character to bind drug-like ligands saves research time and money.While there are a variety of experimental and computational techniques to identify and characterize binding sites, the focus of this chapter is on Binding Site Analysis (BSA) using virtual fragment simulations. The methodology of the technique is described, along with examples of successful application to drug discovery programs. BSA both indicates if a protein is a viable target for drug discovery and provides a roadmap for designing ligands. Using a computational fragment-based method is a effective means of understanding of a binding site.

Synthesis, X-ray Structure Determination, and Comprehensive Photochemical Characterization of (Trifluoromethyl)diazirine-Containing TRPML1 Ligands

“…However, the exact location of the binding site of MK6–83 could not yet be determined, and currently, only cryo-EM structures of TRPML1 and TRPML3, respectively, bound with the nonselective and (structurally) different agonist (ML-SA1 ( 2 ), Figure ) , are available. , It is not unambiguously clarified if MK6–83 addresses the same binding site within the channel and which key interactions are underlying to explain its different TPRML selectivity and activation profile compared to ML-SA1 . For rational structure-based design and development of new drug molecules, an in-depth understanding of ligand-target recognition and the interaction between the receptor protein and its small-molecule ligand is essential. , In the past decades, photoaffinity labeling (PAL) has emerged as a very powerful tool in medicinal chemistry and chemical biology for studying ligand-target interactions and to provide additional information on the binding pocket and the amino acid residues involved in drug binding. − This valuable technique exploits the intrinsic property of ligands featuring a photoreactive group (PRG) to produce a highly reactive species (e.g., a carbene), which, after the formation of a particular noncovalent ligand–receptor complex, covalently and irreversibly binds to proximate residues within the binding site during photolysis by irradiation with a specific wavelength of light. ,,, In this study, we focused on the synthesis as well as structural determination of novel (trifluoromethyl)­diazirine-containing TRPML1 activators and extensively investigated their photochemical insertion reactivity in different solvents. These stable and useful photoactivatable analogues of MK6–83 may allow the identification of the binding site within the TRPML1 channel and thus make a relevant contribution to the elucidation of the molecular mechanisms involved in the specific ligand-protein interaction between the TRPML1 activator and its target ion channel.…”

The immunogenicity and protective immunity of multi-epitopes DNA prime-protein boost vaccines encoding Amastin-Kmp-11, Kmp11-Gp63 and Amastin-Gp63 against visceral leishmaniasis

“…Based on the results of bioinformatics analysis of Amastin, Kmp-11 and Gp63 proteins, the epitope-based vaccine Amastin-Gp63, Amastin-Kmp-11 and Kmp-11-Gp63 had a high antigenic index and they were rich in HLA-A24, HLA-A2, HLA-DR1 and H2-D epitopes. The existence of potential binding sites in Amastin-Gp63 and Kmp-11-Gp63 works on the interaction of epitopes with the antigen-presenting cells [53,54], suggesting its immunogenicity. HLA class Ⅰ molecules are involved in the presentation of endogenous antigens, activate CD8 + cells, and participate in cellular immunity.…”