A Pilot Study of All-Computational Drug Design Protocol-From Structure Prediction to Interaction Analysis

• Published in: Frontiers in chemistry Vol. 8; p. 81
• Main Authors: Wu, Yifei, Lou, Lei, Xie, Zhong-Ru
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 12.02.2020
• Subjects: binding site prediction; Chemistry; computational drug discovery; ligand-protein docking; molecular dynamics simulation; SK2; structural prediction; pharmaceutical industry; structural prediction; computational drug discovery; virtual mutation; molecular dynamics simulation; binding site prediction; ligand-protein docking; SK2
• ISSN: 2296-2646; 2296-2646
• DOI: 10.3389/fchem.2020.00081

Speeding up the drug discovery process is of great significance. To achieve that, high-efficiency methods should be exploited. The conventional wet-bench methods hardly meet the high-speed demand due to time-consuming experiments. Conversely, approaches are much more efficient for drug discovery and design. However, approaches usually serve as a supportive role in research processes. To fully exert the strength of computational methods, we propose a protocol which integrates various approaches, from protein structure prediction to ligand-protein interaction simulation. As a proof of concept, human SK2/calmodulin complex was used as a target for validation. First, we obtained a predicted structure of SK2/calmodulin and predicted binding sites which were consistent with the literature data. Then we investigated the ligand-protein interaction via virtual mutagenesis, flexible docking, and binding affinity calculation. As a result, the binding energies of mutants have similar trends compared with the EC values ( = 0.6 for NS309 in V481 mutants). The results indicate that our protocol can be applied to the drug design of structure unknown proteins. Our study also demonstrates that the integration of approaches is feasible and it facilitates the acceleration of new drug discovery.