In Silico Critical Residues Evaluation and Improvement

Although monoclonal antibodies (mAbs) have gained a significant share of the pharmaceutical market and the number of mAbs in clinical trials continues to increase, the path from laboratory science to the final drug product is often hindered by substantial roadblocks arising from unfavorable, but intrinsic, molecular properties. Thus, drug-based analysis is a very important part of drug design. Computer simulations have shown great potential in it, considering developability-related issues early in the drug discovery phase, and involving the rational design of antibodies to obtain favorable manufacturing and control properties. Creative Biolabs has developed the in silico method based on the development of critical residue-based predictability to help the successful development of drugs.

Background of Critical Residues

In recent decades, therapeutic antibodies and antibody-like molecules have formed a big class of newly approved drugs. Currently, clinical trials of these drugs are still growing rapidly. A therapeutic protein that can be commercialized successfully should not only have the anticipated efficacy, safety, and pharmacokinetics, but also have the physicochemical properties of drug samples to ensure its stability to meet the technical requirements of manufacturing and pharmaceutical processes. In fact, the amino acid sequence of proteins determines the folding and final structure of macromolecules. It has been proposed that by identifying critical residues in the atomic structure of proteins, a critical stability framework can be selected, which is essential for the correct folding of proteins. Currently, global computational mutations based on unfolded mutation screens are used to test the effect of each possible missense mutation on protein structure in order to identify residues that cannot tolerate replacement without causing protein misfolding. It is very important to guide the optimization of antibodies in order to improve the stability of the formulation.

In Silico Critical Residues Evaluation and Improvement in Creative Biolabs

Critical residue frameworks can be used in genetic engineering to improve small molecule binding in drug research, identify functional diseases that cause missense mutations in gene research, and help identify templates for homology models. In silico method has been used to simulate the stability of critical residues of genetic disease-related proteins. It has been proved that critical residues of mutation have a significant effect on the stability of genetic disease-related proteins when critical residues exist.

Fig.1 Examples of in silico prediction and design. (Aamir, 2018)

For example, in ophthalmopathy, myoglobin was used to verify the conservativeness of critical residues, and the critical residues of six different crystal structures were identical. The conservativeness of key residues was compared with that of nine ophthalmopathy-related proteins. Studies have shown that a key protein stability framework can be determined by selecting key elements in protein structure. These computational studies play a key role in the study of ophthalmic diseases. Information on the risk of protein instability due to changes in protein stability and gene mutations is provided, which is obtained from the atomic level of protein structure on silicon wafers. The simulated loci can be used as a tool for the analysis of new mutation expression in experimental biochemistry. It is possible to use these data in clinical practice, next-generation sequencing, genotype-phenotype relationship of hereditary ophthalmopathy, and powerful basis for drug-formulation evaluation and optimization.

Our goal is to help assess and improve the possibilities of critical residues in drug treatment. We have made some progress by in silico method. If you are interested in our service, please feel free to contact us.

Reference

Aamir, M.; et al. In silico Prediction, Characterization, Molecular Docking and Dynamic Studies on Fungal SDRs as Novel Targets for Searching Potential Fungicides against Fusarium Wilt in Tomato. Frontiers in pharmacology. 2018, 9: 1038.

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