Flap‐site Fragment Restores Back Wild‐type Behaviour in Resistant Form of HIV Protease

Luchi, Adriano Martín; Angelina, Emilio; Bogado, Lucrecia; Forli, Stefano; Olson, Arthur J.; Peruchena, Nélida María

doi:10.1002/minf.201800053

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…We have previously applied this theory to understand the action mechanism of human dihydrofolate reductase inhibitors, , BACE1 inhibitors, , D2 dopamine receptor ligands, − sphingosine kinase 1 (Sphk1) inhibitors, and HIV-1 protease flap fragments, among others.…”

Section: Introductionmentioning

confidence: 99%

Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism

et al. 2019

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Trypanosoma cruzi, a flagellate protozoan parasite, is responsible for Chagas disease. The parasite major cysteine protease, cruzain (Cz), plays a vital role at every stage of its life cycle and the active-site region of the enzyme, similar to those of other members of the papain superfamily, is well characterized. Taking advantage of structural information available in public databases about Cz bound to known covalent inhibitors, along with their corresponding activity annotations, in this work, we performed a deep analysis of the molecular interactions at the Cz binding cleft, in order to investigate the enzyme inhibition mechanism. Our toolbox for performing this study consisted of the charge density topological analysis of the complexes to extract the molecular interactions and machine learning classification models to relate the interactions with biological activity. More precisely, such a combination was useful for the classification of molecular interactions as “active-like” or “inactive-like” according to whether they are prevalent in the most active or less active complexes, respectively. Further analysis of interactions with the help of unsupervised learning tools also allowed the understanding of how these interactions come into play together to trigger the enzyme into a particular conformational state. Most active inhibitors induce some conformational changes within the enzyme that lead to an overall better fit of the inhibitor into the binding cleft. Curiously, some of these conformational changes can be considered as a hallmark of the substrate recognition event, which means that most active inhibitors are likely recognized by the enzyme as if they were its own substrate so that the catalytic machinery is arranged as if it is about to break the substrate scissile bond. Overall, these results contribute to a better understanding of the enzyme inhibition mechanism. Moreover, the information about main interactions extracted through this work is already being used in our lab to guide docking solutions in ongoing prospective virtual screening campaigns to search for novel noncovalent cruzain inhibitors.

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Section: Introductionmentioning

confidence: 99%

Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism

et al. 2019

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Unveiling a Hidden Pocket in HIV‐1 Protease: New Insights Into Retroviral Protease Cantilever‐Tip Region Characteristics

Sherry,

Sayed

2024

Proteins

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The HIV‐1 protease is critical for the process of viral maturation and as such, it is one of the most well characterized proteins in the Protein Data Bank. There is some evidence to suggest that the HIV‐1 protease is capable of accommodating small molecule fragments at several locations on its surface outside of the active site. However, some pockets on the surface of proteins remain unformed in the apo structure and are termed “cryptic sites.” To date, no cryptic sites have been identified in the structure of HIV‐1 protease. Here, we characterize a novel cryptic cantilever pocket on the surface of the HIV‐1 protease through mixed‐solvent molecular dynamics simulations using several probes. Interestingly, we noted that several homologous retroviral proteases exhibit evolutionarily conserved dynamics in the cantilever region and possess a conserved pocket in the cantilever region. Immobilization of the cantilever region of the HIV‐1 protease via disulfide cross‐linking resulted in curling‐in of the flap tips and the propensity for the protease to adopt a semi‐open flap conformation. Structure‐based analysis and fragment‐based screening of the cryptic cantilever pocket suggested that the pocket may be capable of accommodating ligand structures. Furthermore, molecular dynamics simulations of a top scoring fragment bound to the cryptic pocket illustrated altered flap dynamics of the fragment‐bound enzyme. Together, these results suggest that the mobility of the cantilever region plays a key role in the global dynamics of retroviral proteases. Therefore, the cryptic cantilever pocket of the HIV‐1 protease may represent an interesting target for future in vitro studies.

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Elasticity-Associated Functionality and Inhibition of the HIV Protease

Sherry

Worth

Sayed

2021

Advances in Experimental Medicine and Biology

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Flap‐site Fragment Restores Back Wild‐type Behaviour in Resistant Form of HIV Protease

Cited by 3 publications

References 25 publications

Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism

Combining Charge Density Analysis with Machine Learning Tools To Investigate the Cruzain Inhibition Mechanism

Unveiling a Hidden Pocket in HIV‐1 Protease: New Insights Into Retroviral Protease Cantilever‐Tip Region Characteristics

Elasticity-Associated Functionality and Inhibition of the HIV Protease

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