@article{Valdés-Albuernes2026,

title = {Computational modeling of ubiquitin specific protease 7 (USP7) complexes with N-benzylpiperidinol derivatives incorporating binding site flexibility},

author = {Jorge Luis Valdés-Albuernes and Erbio Díaz-Pico and José Luis Velázquez-Libera and Julio Caballero },

doi = {10.1016/j.jmgm.2025.109272},

year  = {2026},

date = {2026-01-08},

abstract = {Ubiquitin-specific protease 7 (USP7) is a key regulator of protein homeostasis, playing critical roles in various cellular processes, including DNA damage response, immune signaling, and oncogenesis. Targeting USP7 with small-molecule inhibitors has emerged as a promising therapeutic strategy, particularly in the context of cancer and autoimmune diseases. Among the diverse scaffolds explored for USP7 inhibition, N-benzylpiperidinol (NBP) derivatives have shown notable potential due to their structural versatility and bioactivity. Computationally, it is possible to access models of complexes between these inhibitors and USP7 by utilizing the crystallographic structures of USP7 available in the Protein Data Bank. In a classical approach, models of NBPs can be obtained within a rigid USP7 structure. In this work, we report models of complexes between 58 NBPs and variable conformations of USP7 using a flexible docking protocol employing the novel CorrEA method. As part of this protocol, we obtained diverse USP7 structures through molecular dynamics (MD) and selected complex models with inhibitors based on their biological activities. Model quality was validated using LigRMSD and interaction fingerprints (IFP). The flexible treatment of USP7 enabled the capture of binding-site conformational changes. These changes are critical for explaining the activity differences among the studied compounds.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Unraveling Lewis base substitution in ansa-type frustrated Lewis pairs: how N → P replacement redefines adduct stability and H2 activation},

author = {César Barrales-Martínez and Javier Rosales-Rojas and Julio Caballero and Rocío Durán },

doi = {10.1039/d5ra06998j },

year  = {2025},

date = {2025-10-21},

urldate = {2025-10-21},

abstract = {This study investigates, through quantum-chemical calculations, how replacing nitrogen with phosphorus in ansa-type frustrated Lewis pairs reshapes both the FLP–CLA equilibrium and H2 activation thermodynamics. Energy decomposition analysis shows that the stabilization of ansa-phosphinoborane adducts arises mainly from steric relief, which compensates for weaker donor–acceptor interactions. For H2 activation, the energetic effect of Lewis base substitution reaches up to 35.9 kcal mol−1 and correlates directly with the proton affinity differences between the corresponding amines and phosphines. This correlation identifies proton affinity as a predictive descriptor of reactivity. By establishing how N → P substitution redefines the steric–electronic balance controlling adduct stability and H2 cleavage, this work provides conceptual design principles for tailoring frustrated Lewis pairs. These insights advance the molecular-level understanding of main-group systems and support the rational development of next-generation metal-free hydrogenation catalysts under sustainable conditions.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Valdés-Albuernes2025,

title = {Advanced modeling of salt-inducible kinase (SIK) inhibitors incorporating protein flexibility through molecular dynamics and cross-docking},

author = {Jorge Luis Valdés-Albuernes and Erbio Díaz-Pico and Sergio Alfaro and Julio Caballero},

doi = {10.1038/s41598-025-03699-w},

year  = {2025},

date = {2025-05-29},

urldate = {2025-05-29},

abstract = {Salt-inducible kinases (SIK1, SIK2, and SIK3) regulate metabolism and immune responses, making them promising targets for inflammatory and autoimmune diseases. Understanding inhibitor selectivity among isoforms is crucial for therapeutic development. In this study, 44 compounds were investigated as SIK inhibitors using molecular modeling. A flexible treatment of the kinases via molecular dynamics (MD) simulations captured binding site conformational changes, followed by molecular docking to generate protein kinase (PK)-ligand complex models. Ligand orientations were validated against crystallographic data using LigRMSD and interaction fingerprints (IFPs). A genetic algorithm was applied to select conformations that maximize correlation between docking energies and biological activities, yielding R² values of 0.821, 0.646, and 0.620 for SIK1, SIK2, and SIK3, respectively. Our results highlight the importance of protein flexibility in achieving accurate correlations between docking energies and experimental pIC50 values, enhancing inhibitor selectivity predictions.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{valdes-albuernes_modeling_2024,

title = {Modeling of noncovalent inhibitors of the papain-like protease (PLpro) from SARS-CoV-2 considering the protein flexibility by using molecular dynamics and cross-docking},

author = {Jorge Luis Valdés-Albuernes and Erbio Díaz-Pico and Sergio Alfaro and Julio Caballero},

url = {https://www.frontiersin.org/articles/10.3389/fmolb.2024.1374364/full},

doi = {10.3389/fmolb.2024.1374364},

issn = {2296-889X},

year  = {2024},

date = {2024-03-01},

urldate = {2024-12-14},

journal = {Frontiers in Molecular Biosciences},

volume = {11},

pages = {1374364},

abstract = {The papain-like protease (PLpro) found in coronaviruses that can be transmitted from animals to humans is a critical target in respiratory diseases linked to Severe Acute Respiratory Syndrome (SARS-CoV). Researchers have proposed designing PLpro inhibitors. In this study, a set of 89 compounds, including recently reported 2-phenylthiophenes with nanomolar inhibitory potency, were investigated as PLpro noncovalent inhibitors using advanced molecular modeling techniques. To develop the work with these inhibitors, multiple structures of the SARS-CoV-2 PLpro binding site were generated using a molecular sampling method. These structures were then clustered to select a group that represents the flexibility of the site. Subsequently, models of the protein-ligand complexes were created for the set of inhibitors within the chosen conformations. The quality of the complex models was assessed using LigRMSD software to verify similarities in the orientations of the congeneric series and interaction fingerprints to determine the recurrence of chemical interactions. With the multiple models constructed, a protocol was established to choose one per ligand, optimizing the correlation between the calculated docking energy values and the biological activities while incorporating the effect of the binding site’s flexibility. A strong correlation (R 

 2 = 0.922) was found when employing this flexible docking protocol.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{barrales-martinez_exploring_2024,

title = {Exploring the electronic and steric effects on the dimerization of intramolecular frustrated Lewis pairs: a comparison between aminoboranes and aminoalanes},

author = {César Barrales-Martínez and Claudio Illanes-Solis and Rocío Durán and Julio Caballero},

url = {https://xlink.rsc.org/?DOI=D3DT04274J},

doi = {10.1039/D3DT04274J},

issn = {1477-9226, 1477-9234},

year  = {2024},

date = {2024-01-01},

urldate = {2025-01-02},

journal = {Dalton Transactions},

volume = {53},

number = {16},

pages = {7000–7011},

abstract = {The dimerization of intramolecular aminoborane and aminoalane frustrated Lewis pairs was investigated using density functional theory. 

 , 

 The dimerization of intramolecular aminoborane and aminoalane frustrated Lewis pairs was investigated using density functional theory. We systematically varied the substituents to gradually increase their bulkiness, including H, CH 

 3 

 , 

 t 

 -Bu, Ph, and Mes groups. Starting from the most stable conformer of the monomers, a frustrated Lewis pair or classic Lewis adduct, we studied the dimerization process for all systems, revealing significant variations in the Gibbs free energy. Dimerization was favored in four aminoboranes and six aminoalanes, depending on the specific combinations of substituents. Applying an energy decomposition analysis, we found that the preparation energy of the monomers and the non-orbital interactions between them are the primary contributors to the observed energetic differences, showing a clear linear relationship. Additionally, we analyzed the electronic effects by increasing the acidity of the Lewis acid, observing a shift toward endergonic and exergonic directions in aminoboranes and aminoalanes, respectively. This shift was attributed to the stabilization of a classic Lewis adduct. This study underscores three crucial factors influencing dimer formation: (i) substituent size, (ii) stabilization of the classic Lewis adduct conformation, and (iii) covalent radii of the Lewis centers. Understanding these factors is essential for designing FLPs and preventing unwanted dimerization that could affect their catalytic performance in H 

 2 

 activation processes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{González-Avendaño2023,

title = {Assessing mitochondria-targeted acyl hydroquinones on the mitochondrial platelet function and cytotoxic activity: Role of the linker length},

author = {Mariela González-Avendaño and Hector Montecino-Garrido and Magdalena Sepúlveda and Diego Méndez and Matías Monroy-Cárdenas and Sergio Alfaro and Julio Caballero and Felix A Urra and Ramiro Araya-Maturana and Eduardo Fuentes},

doi = {10.1016/j.freeradbiomed.2023.07.030},

year  = {2023},

date = {2023-11-01},

urldate = {2023-11-01},

abstract = {The use of triphenylphosphonium cation (TPP+) linked to phenolic compounds by alkyl chains has a significant relevance as a mitochondrial delivery strategy in biomedicine because it affects mitochondrial bioenergetics in models of noncommunicable diseases such as cancer and cardiovascular-related conditions. Studies indicate that a long alkyl chain (10-12 carbon) increases the mitochondrial accumulation of TPP+-linked drugs. In contrast, other studies show that these compounds are consistently toxic to micromolar concentrations (as observed in platelets). In the present study, we evaluated the in vitro effect of three series of triphenylphosphonium-linked acyl hydroquinones derivates on the metabolism and function of human platelets using 3-9 carbons for the alkyl linker. Those were assessed to determine the role of the length of the alkyl chain linker on platelet toxicity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Rossino2021,

title = {Bitopic Sigma 1 Receptor Modulators to Shed Light on Molecular Mechanisms Underpinning Ligand Binding and Receptor Oligomerization},

author = {Giacomo Rossino and Marta Rui and Pasquale Linciano and Daniela Rossi and Massimo Boiocchi and Marco Peviani and Elena Poggio and Daniela Curti and Dirk Schepmann and Bernhard Wunsch and Mariela González-Avendaño and Ariela Vergara-Jaque and Julio Caballero and Simona Collina},

doi = {10.1021/acs.jmedchem.1c00886},

year  = {2021},

date = {2021-10-08},

urldate = {2021-10-08},

abstract = {The sigma 1 receptor (S1R) is an enigmatic ligand-operated chaperone involved in many important biological processes, and its functions are not fully understood yet. Herein, we developed a novel series of bitopic S1R ligands as versatile tools to investigate binding processes, allosteric modulation, and the oligomerization mechanism. These molecules have been prepared in the enantiopure form and subjected to a preliminary biological evaluation, while in silico investigations helped to rationalize the results. Compound 7 emerged as the first bitopic S1R ligand endowed with low nanomolar affinity (Ki = 2.6 nM) reported thus far. Computational analyses suggested that 7 may stabilize the open conformation of the S1R by simultaneously binding the occluded primary binding site and a peripheral site on the cytosol-exposed surface. These findings pave the way to new S1R ligands with enhanced activity and/or selectivity, which could also be used as probes for the identification of a potential allosteric site.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Rossino2019,

title = {New Insights into the Opening of the Occluded Ligand-Binding Pocket of Sigma1 Receptor: Binding of a Novel Bivalent RC-33 Derivative},

author = {Giacomo Rossino and Ivana Orellana and Julio Caballero and Dirk Schepmann and Bernhard Wunsch and Marta Rui and Daniela Rossi and Mariela González-Avendaño and Simona Collina and Ariela Vergara-Jaque},

doi = {10.1021/acs.jcim.9b00649},

year  = {2019},

date = {2019-12-06},

urldate = {2019-12-06},

abstract = {Significant progresses have been made to understand the molecular basis of the Sigma1 receptor (S1R) operating in normal and pathological conditions. S1R is a transmembrane protein that participates in a wide variety of processes at the central nervous system; hence, its function has been associated with mental and neurological disorders. Several ligands have been proposed to regulate the function of S1R revealing a high plasticity of the ligand-binding pocket. Previous drug-design studies have been mainly based on pharmacophore models; however, the recently revealed crystal structure of S1R provides an excellent opportunity for verifying previous predictions and for evaluating the binding of novel compounds. Interestingly, the crystal structure shows that the binding pocket of S1R is highly occluded from solvent; therefore, it is not clear how ligands access this site. In the present work, we applied steered molecular dynamics (SMD) simulations to open the occluded ligand-binding pocket in the S1R crystal structure and to determine the preferred ligand pathway to enter and exit the binding site. The intracellular surface of the β-barrel ligand-binding region was found the most favorable route to accommodate ligands. This route supports the binding of RC-33 (our in-house-developed S1R modulator) and a new bivalent derivative that constitutes the first divalent structure shown to interact with S1R. Free energy calculations of these compounds associated with S1R agree with experimental Ki values and provide molecular insights of the binding mode of modulators that could access the S1R ligand-binding pocket through the cytoplasmic region.



},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{nokey,

title = {Computational modeling of ubiquitin specific protease 7 (USP7) complexes with N-benzylpiperidinol derivatives incorporating binding site flexibility},

author = {Jorge Luis Valdés-Albuernes and Erbio Díaz-Pico and José Luis Velázquez-Libera and Julio Caballero},

doi = {10.1016/j.jmgm.2025.109272},

abstract = {Ubiquitin-specific protease 7 (USP7) is a key regulator of protein homeostasis, playing critical roles in various cellular processes, including DNA damage response, immune signaling, and oncogenesis. Targeting USP7 with small-molecule inhibitors has emerged as a promising therapeutic strategy, particularly in the context of cancer and autoimmune diseases. Among the diverse scaffolds explored for USP7 inhibition, N-benzylpiperidinol (NBP) derivatives have shown notable potential due to their structural versatility and bioactivity. Computationally, it is possible to access models of complexes between these inhibitors and USP7 by utilizing the crystallographic structures of USP7 available in the Protein Data Bank. In a classical approach, models of NBPs can be obtained within a rigid USP7 structure. In this work, we report models of complexes between 58 NBPs and variable conformations of USP7 using a flexible docking protocol employing the novel CorrEA method. As part of this protocol, we obtained diverse USP7 structures through molecular dynamics (MD) and selected complex models with inhibitors based on their biological activities. Model quality was validated using LigRMSD and interaction fingerprints (IFP). The flexible treatment of USP7 enabled the capture of binding-site conformational changes. These changes are critical for explaining the activity differences among the studied compounds.

},

keywords = {},

pubstate = {forthcoming},

tppubtype = {article}

}