Abstract
Biobetters are new drugs designed from existing peptide or protein-based therapeutics by improving their properties such as affinity and selectivity for the target epitope, and stability against degradation. Computational methods can play a key role in such design problems—by predicting the changes that are most likely to succeed, they can drastically reduce the number of experiments to be performed. Here we discuss the computational and experimental methods commonly used in drug design problems, focusing on the inverse relationship between the two, namely, the more accurate the computational predictions means the less experimental effort is needed for testing. Examples discussed include efforts to design selective analogs from toxin peptides targeting ion channels for treatment of autoimmune diseases and monoclonal antibodies which are the fastest growing class of therapeutic agents particularly for cancers and autoimmune diseases.
Highlights
Protein-Ligand Complex Structure from Docking and molecular dynamics (MD)Determination of crystal structures for protein-ligand complexes is extremely difficult and very rare
Biobetters are new drugs designed from existing peptide or protein-based therapeutics by improving their properties such as affinity and selectivity for the target epitope, and stability against degradation
Potassium channels are targeted by many toxins, which could be utilized as therapeutics in treatment of diseases caused by their dysfunction [57]
Summary
Determination of crystal structures for protein-ligand complexes is extremely difficult and very rare. Assuming crystal or NMR structures (or good homology models) of the protein and ligand are available, one can use a docking program to find a set of initial poses for the complex [4,5]. Accuracy of docking programs is limited due to neglect of water molecules and lack of adequate sampling [11] These are automatically incorporated in MD simulations, MD has the capacity to provide an accurate representation of the protein-ligand interactions. A compromise solution is to refine the binding poses predicted by docking in MD simulations, which avoids the shortcomings of either method and could provide the sought accuracy This approach was first used for binding of small ligands (b50 at.), and promising results were obtained [1,12,13,14]. Alanine scanning experiments are available only in a few cases, and one has to rely on binding free energies for validation in most cases
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