ABSTRACT
Proteins and their complexes can be appreciated as molecular machines with an elaborate three-dimensional (3D) structure, carrying out particular tasks along the complex biological pathways effective in the physiology of the organism.1 Such a
2.1 Introduction .................................................................................................... 35 2.2 Computational Technologies for Protein Therapeutic Optimization ............. 37
2.2.1 Model Building and Structural Analysis ............................................ 37 2.2.2 Simulation of Conformational Change and Dynamics .......................40 2.2.3 Energy Function and Scoring ............................................................. 41
2.3 Application of Computational Methods for Protein Therapeutic Optimization ................................................................................................... 43 2.3.1 Target Discovery and Computational Methods .................................. 43 2.3.2 Modalities of Biologic Action .............................................................44 2.3.3 Optimization of Insulin ...................................................................... 45 2.3.4 Pharmacokinetic Optimization ...........................................................46 2.3.5 FcRn Receptor and Biologics .............................................................48 2.3.6 Fcγ Receptor (FcγR) Afnity Modulation ..........................................48 2.3.7 Fc Fusion and Dimerization ............................................................... 49 2.3.8 Bispecic Antibodies .......................................................................... 49 2.3.9 Heterodimeric Fc Engineering ...........................................................50 2.3.10 Antibody Variable Domain Modeling ................................................ 51 2.3.11 Drug Delivery System ........................................................................ 52
2.4 Conclusions ..................................................................................................... 53 Acknowledgment .....................................................................................................54 References ................................................................................................................54
perspective of proteins-their structure, interactions, and function-is an essential element of most modern drug discovery efforts. The developments in biological and biochemical sciences in the last century have fostered drug development activity away from empirical discovery and toward a rational knowledge-and data-driven approach.2 Albeit, it is thought provoking that a serendipitous nd remains a valuable element of drug discovery3 and is an indicator of the complexity of the biological organism. Work across the areas of genomics and molecular biology combined with biochemistry, crystallography, and physical chemistry of proteins is providing the necessary knowledge base to advance a mechanistic perspective of protein action and its role in human diseases.
