Abstract

Background: The functions of all proteins in the biological world are attributed to their flexibility. The highly dynamical nature of proteins allows the binding of various endogenous ligands and substrates that are essential to carry out normal functions in all organisms. Since proteins play an indispensable role in the chemistry that sustains life, it is imperative to understand their functions and more importantly their dynamic behavior and harness this knowledge to design effective chemical agents as therapeutic aids.

Objective: The purpose of this review is to discuss the importance of considering flexibility in molecular modeling tools, particularly molecular docking and Quantitative Structure-Activity Relationship (QSAR), to accurately predict the binding conformation of drugs to their protein targets. More emphasis is laid on understanding the importance of modeling protein flexibility of crucial HIV-1 protein targets that has led to the design of potent anti-HIV drugs by molecular docking and QSAR.

Conclusion: We have emphasized the importance of incorporating receptor flexibility in molecular docking and QSAR studies. The benefits of allowing receptor flexibility during docking small molecules are vividly evident as the rate of picking false positives is significantly reduced. Similarly, the mechanism of binding and the type of interactions that dominate to exhibit tight binding can be explained by higher dimensional QSAR models, i.e., 4D-QSAR, which includes conformational flexibility.

Keywords: Protein flexibility, molecular docking, QSAR, molecular dynamics, ensemble docking, HIV-1 reverse transcriptase, HIV-1 protease, HIV-1 integrase.

Graphical Abstract