In-Silico Design of Potent Therapeutic Agents Against Dihydropteroate Synthase, Sars-Cov2, and Pre-Fibrillar Prion Amyloidosis

Abstract

Proteins are central to all biological processes, and their interaction with themselves or other small molecules modulate their function in metabolic, cellular signalling, and immune reactions. Due to their crucial role in biological processes, protein interactions regulate the mechanism of the disease state of organisms and are often targeted by therapeutic agents. However, the major bottleneck in the process of therapeutic design is the lack of structural knowledge regarding the targeted receptors and their dynamic behavior at atomic resolution. The recent advancement in computer technologies and their amalgamation with the chemical and biological processes made a remarkable impact in reducing the cost and complexity of drug discovery processes. The reduction of complexity in computer models helps to understand the underlying interaction and stabilizing forces of drug-receptor complexes. Additionally, the in-silico mutagenesis approach allows for testing the efficacy of therapeutic candidates against drug-resistant mutations. The present research illustrates how ligand-based and Molecular dynamics (MD) assisted structure-based techniques can be combined to design potent therapeutics in three different protein targets, such as a bacterial Dihydropteroate Synthase, spike protein of SARS-Cov2, and abnormal peptide aggregation. It is evident from the results that the stability of small organic molecules or peptide epitopes depends on the number of polar functional groups or amino acids involved in the interaction interface. In both cases, the electrostatic energy contribution is comparatively higher than the Van der Waals energy contribution. In the case of peptide aggregation, such interactions can be replaced by small organic molecules to increase the thermodynamic barriers for inhibiting amyloidosis. The insights obtained from the present research work provide a comprehensive strategy to accelerate the highly challenging drug discovery process.