Jans Alzate-Morales

Jans Alzate-Morales
Universidad de Talca · Center for Bioinformatics Simulations and Modeling (CBSM)

Pharmaceutical chemist, Ph.D

About

75
Publications
11,202
Reads
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1,048
Citations
Citations since 2017
31 Research Items
654 Citations
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2017201820192020202120222023020406080100120140
2017201820192020202120222023020406080100120140
2017201820192020202120222023020406080100120140
Introduction
Our research focuses on studying and understanding the physicochemical phenomena, sometimes intricate and subtle, that occur at the intra- and intermolecular level in protein-drug interaction, protein-substrate recognition, and enzymatic catalysis. To do this, we use various computational tools, such as molecular docking, molecular dynamics, quantum chemistry methods, and hybrid QM / MM (Quantum Mechanics / Molecular Mechanics) calculations, among others.
Additional affiliations
June 2019 - June 2022
Universidad de Talca
Position
  • Research Sponsor
Description
  • "Modelado computacional de variantes Cry11Aa de Bacillus thuringiensis y sus interacciones con receptores de membrana ALP1 y Caderina de Aedes aegypti". FONDECYT Postdoctoral No. 3190852
April 2018 - March 2021
Universidad de Talca
Position
  • Principal Investigator
Description
  • Estimating residence time in protein-ligand complexes: New computational protocols for understanding binding kinetics of drugs, FONDECYT Regular No. 1181253
March 2018 - March 2021
Universidad de Talca
Position
  • Research Sponsor
Description
  • “EVALUATION OF THE MOLECULAR STABILITY OF CYLINDRIN-LIKE STRUCTURES VIA MICROSECOND MOLECULAR DYNAMICS SIMULATIONS” FONDECYT Postdoctoral No. 3180321
Education
March 2002 - December 2006
University of Chile
Field of study
  • Chemical Sciences
March 1995 - June 2001
University of Antioquia
Field of study
  • Health sciences

Publications

Publications (75)
Article
Full-text available
A conformational selection method, based on hydrogen bond (Hbond) network analysis, has been designed in order to rationalize the configurations sampled from molecular dynamics (MD), which are commonly used in the estimation of relative binding free energy of ligands to macromolecules through MM/GBSA or MM/PBSA methods. The approach makes use of pr...
Article
Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions...
Article
Full-text available
Cyclin-dependent kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and prote...
Article
Protein kinase A has become a model system for the study of kinases, and therefore a comprehensive understanding of the underlying molecular mechanisms in its catalytic cycle is of crucial importance. One of the aspects that has received recent attention is the role that metal cofactors play in the catalytic cycle. Although Mg2+ is the well-known p...
Article
Mg 2+ ions are essential for the proper functioning of protein kinases, and their roles in kinase activity have been studied for years. However, recent investigations have shed light on how these metal cofactors modulate the catalytic activity, and other functions for them have been assigned. As an example, it has been found that in cyclin-dependen...
Article
Full-text available
Copper (Cu) nanofluids (NFs) have attracted attention due to their high thermal conductivity, which has conferred a wide variety of applications. However, their high reactivity favors oxidation, corrosion and aggregation, leading them to lose their properties of interest. Copper capped by graphene (Cu@G) core@shell nanoparticles (NPs) have also att...
Article
Full-text available
Pseudomonas aeruginosa is a highly pathogenic Gram-negative microorganism associated with high mortality levels in burned or immunosuppressed patients or individuals affected by cystic fibrosis. Studies support a colonization mechanism whereby P. aeruginosa can breakdown the host cell membrane phospholipids through the sequential action of two enzy...
Preprint
Full-text available
The accurate experimental estimation of residence time (τ) of protein-ligand systems has become very relevant in drug design projects (1) due to its importance in the last stages of refinement of the drug's pharmacodynamics and pharmacokinetics (2). It is now well known that it is not sufficient to estimate the affinity of a protein-drug complex in...
Article
Enzymes with hydroxymethylpyrimidine/phosphomethylpyrimidine kinase activity (HMPPK) are essential in the vitamin B1 (thiamine pyrophosphate) biosynthesis and recycling pathways. In contrast, enzymes with pyridoxal kinase activity (PLK) produce pyridoxal phosphate (vitamin B6), an essential cofactor for various biochemical reactions. In the ATP‐dep...
Article
Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges in achieving an accurate structural and dynamical description of many biological assemblies, particularly to coarse-grained (CG) models. Although the reduced computational cost of CG met...
Preprint
div>In this contribution, the phosphoryl transfer reaction in CDK2 has been studied in detail considering the presence of an additional Mg2+ ion in the active site. For this purpose, QM/MM (quantum mechanics/molecular mechanics) free energy calculations with the adaptive string method were performed, which showed that indeed the system containing t...
Article
The hydroxymethylpyrimidine phosphate kinases (HMPPK) encoded by the thiD gene and involved in the thiamine biosynthesis pathway, can perform two consecutive phosphorylations of 4-amino-5-hydroxymethyl-2-methyl pyrimidine (HMP) and are found in thermophilic and mesophilic bacteria, and only a few characterizations of mesophilic enzymes are availabl...
Preprint
p>Although molecular dynamics simulations allow for the study of interactions among virtually all biomolecular entities, metal ions still pose significant challenges to achieve an accurate structural and dynamical description of many biological assemblies. This is particularly the case for coarse-grained (CG) models. Although the reduced computatio...
Article
Full-text available
A series of 44 hybrid compounds that included in their structure tetrahydroquinoline (THQ) and isoxazole/isoxazoline moieties were synthesized through the 1,3-dipolar cycloaddition reaction (1,3-DC) from the corresponding N-allyl/propargyl THQs, previously obtained via cationic Povarov reaction. In vitro cholinergic enzymes inhibition potential of...
Article
Full-text available
Lignin peroxidase (LiP) and its natural substrate veratryl alcohol (VA) play a crucial role in lignin degradation by white-rot fungi. Understanding the molecular determinants for the interaction of this enzyme with its substrates is essential in the rational design of engineered peroxidases for biotechnological application. Here, we combine computa...
Article
Full-text available
The imino‐Diels‐Alder reaction is one of the most common strategies in organic chemistry and is an important tool for providing a broad spectrum of biologically active heterocyclic systems. A combined theoretical and experimental study of the imino‐Diels‐Alder reaction is described. The new phenanthroline‐tetrahydroquinolines were evaluated as chol...
Preprint
Full-text available
Cyclin-dependent kinase 2 (CDK2) is an important member of the CDK family exerting its most important function in the regulation of the cell cycle. It catalyzes the transfer of the gamma phosphate group from an ATP (adenosine triphosphate) molecule to a Serine/Threonine residue of a peptide substrate. Due to the importance of this enzyme, and prote...
Article
The design of organometallic complexes used as selective intercalators to bind and react at DNA mismatch sites has concentrated efforts the last years. In this context, lanthanides have received attention to be employed as active optical centers due to their spectroscopic properties. Despite there are several experimental data about synthesis and D...
Article
The aim of this work was to compare the anti-inflammatory activity of compounds prepared from terpenes and the synthetic drugs ibuprofen and naproxen. The anti-inflammatory activity of the hybrid compounds was compared with the activity of the parent compounds. This was accomplished using in vitro inhibition of lipoxygenases (LOX) and COX-2, and in...
Article
Full-text available
Phosphofructokinases (Pfks) catalyze the ATP-dependent phosphorylation of fructose-6-phosphate (F6P) and they are regulated in a wide variety of organisms. Although numerous aspects of the kinetics and regulation have been characterized for Pfks, the knowledge about the mechanism of the phosphoryl 15 transfer reaction and the transition state lags...
Article
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, presenting the most devastating consequences on human health and life quality. Coumarin‐quinoline hybrids were synthesized following a very efficient and versatile strategy. Small structural variations contributed to dual acetyl/butyrylcholinesterases (AChE/BuChE) activity or...
Article
Full-text available
Most snake venom toxins are proteins, and participate to envenomation through a diverse array of bioactivities, such as bleeding, inflammation, and pain, cytotoxic, cardiotoxic or neurotoxic effects. The venom of a single snake species contains hundreds of toxins, and the venoms of the 725 species of venomous snakes represent a large pool of potent...
Article
Plants from temperate climates, such as the model plant Arabidopsis thaliana, are challenged with seasonal low temperatures that lead to increased freezing tolerance in fall in a process termed cold acclimation. Among other adaptations, this involves the accumulation of cold-regulated (COR) proteins, such as the intrinsically disordered chloroplast...
Article
Given the wide spectrum of biological uses of pyrazolo[1,5-c]quinazoline and spiro-quinazoline derivatives as anticancer, anti-inflammatory analgesic agents, and their therapeutic applications in neurodegenerative disorders, it is compulsory to find easy, efficient, and simple methods to obtain and chemically diversify these families of compounds,...
Article
Full-text available
Lignin peroxidase (LiP) is an important enzyme for degrading aromatic hydrocarbons not only in nature but also in industry. In the presence of H2O2, this enzyme can easily decompose lignin and analogue compounds under mild conditions. In this reaction mechanism, LiP catalyzes the C–C cleavage of a propenyl side chain, being able to produce veratral...
Chapter
Full-text available
This book chapter will be presented as follow: first, a brief introduction to structure and characterization of lignin and its derivatives is presented, as well as their importance as chemical scaffolds for obtaining value added products in chemical, food, pharmaceutical and agriculture industry. Second, an extensive review of different reports usi...
Article
Non-additivity in noncovalent interactions is an important aspect of complex systems that can lead to stronger (cooperative) interactions when three or more molecular units influence each other. The halogen bond (XB) is a highly-directional noncovalent interaction that has been found to be cooperative. Here the strength and nature of cooperativity...
Article
Full-text available
In this research work a new type of ruthenium sensitizers used in dye sensitized solar cells (DSSCs), named as S3 and S4 and consisting of carbazole secondary electron donor antenna, have been synthesized and characterized by 1H NMR, UV–Vis absorption spectroscopy and elemental analysis. The energy levels and band gap of the sensitizers were evalua...
Conference Paper
Protein kinases are an important family of enzymes that govern many signaling processes within cells by transferring a phosphoryl group from an ATP molecule onto a substrate protein. cAMP-dependent protein kinase, also called protein kinase A (PKA), is one of the most well-studied protein kinases, and because of the high conservation of the protein...
Conference Paper
Lignin peroxidase (LiP), a fungal heme-containing peroxidase, first discovered in the basidiomycete Phanerochaete chrysosporium, plays an important role in the degradation of lignin and lignin model compounds1-3 due to its high redox potential. Veratryl alcohol (VA), is a secondary metabolite of the fungus P. chrysosporium and is the main substrate...
Article
Full-text available
Halogen bonding (XB) is a noncovalent interaction that has been increasingly used in molecular recognition, and more recently, in protein-ligand binding. We have studied and quantified, using density functional theory (DFT) calculations, the substituent effect of fourteen chemical groups in the chloro-, bromo- and iodobenzene···N-methylacetamide (N...
Article
Full-text available
New N-allyl/propargyl 4-substituted 1,2,3,4-tetrahydroquinolines derivatives were efficiently synthesized using acid-catalyzed three components cationic imino Diels–Alder reaction (70–95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl-cholinesterase inhibitors and their potential binding modes, and affinity, were pred...
Article
The LEA (late embryogenesis abundant) proteins COR15A and COR15B from Arabidopsis thaliana are intrinsically disordered under fully hydrated conditions, but obtain α-helical structure during dehydration, which is reversible upon rehydration. To understand this unusual structural transition, both proteins were investigated by circular dichroism (CD)...
Article
Full-text available
Aroma and flavor are important factors of fruit quality and consumer preference. The specific pattern of aroma is generated during ripening by the accumulation of volatiles compounds, which are mainly esters. Alcohol acyltransferase (AAT) (EC 2.3.1.84) catalyzes the esterification reaction of aliphatic and aromatic alcohols and acyl-CoA into esters...
Data
Main distances established between ligands and catalytic residues at the SAAT active site during 5 ns of MD simulations. (A) Distances between the oxygen atom of the alcohols and the carbonylic carbon of the acetyl-CoA (dHO•••O = C-AcCoA); (B) Distances between the oxygen atom of the alcohols and the Nε of the His157 (dHO•••Nε-His157). Distances fo...
Data
Evaluation of non-local environment interactions performed by the atomic empirical mean force potential ANOLEA on each heavy atom in the SAAT model. Negatives energies (on green) represent favorable interactions of the respective residue. (TIFF)
Data
RMSD values of SAAT–acetylCoA–octanol (upper left), SAAT–acetylCoA–hexanol (upper right), SAAT–acetylCoA–benzylalcohol (bottom left) and SAAT–acetylCoA–butanol complexes (bottom right), measured during the 5ns equilibration molecular dynamics simulation. On black is represented the protein backbone, on red the acetylCoA substrate and on green the r...
Data
Sequence alignment between Vironina synthase (Rauvolfia serpentina) and the AAT of Fragaria ananassa. The highly conserved motifs HXXXD and DFGWG are highlighted in yellow. (TIFF)
Data
2D representation of vdW interactions, between octanol and nonpolar groups in SAAT. The purple arrow represent the hydrogen bond interaction made between the hydroxyl group of octanol and the Nε of His157. (TIFF)
Data
Schematic and 3D representations of the solvent channel in SAAT protein. The upper scheme emphasizes the size difference in volume between the front and back faces of the channel. The former allows the binding of acetyl-CoA and the latter the binding of alcohol substrates. Catalytic residues are represented in sticks and the channel as a molecular...
Data
Average distances for electrostatic interactions made between residues Asp166, Arg177, Arg180 and Asn182 with respect acetyl-CoA during a 5 ns MD simulation (see also Fig 2). (PDF)
Article
Full-text available
Veratryl alcohol (VA) is the main substrate of lignin peroxidase (LiP), a key lignin- degrading enzyme. A redox mediator role, in the lignin degradation process, has been attributed to this molecule, however many unanswered questions remain about its action mechanism. In this investigation the basic aspects of a plausible action mechanism, this mea...
Article
Full-text available
Alzheimer disease (AD) is a neurodegenerative disorder that causes damages in brain due to factors such as oxidative stress, low-levels of the neurotransmitter acetylcholine, β-amyloid protein aggregation, etc. It is necessary the design of novel efficient drugs for AD treatment to counteract the increase of people suffering from AD. Recently, hete...
Article
Phenol is one of the worst contaminants at date, and its degradation has been a crucial task over years. Here, the decomposition process of phenol, in a Fenton reaction, is described. Using scavengers, it was observed that decomposition of phenol was mainly influenced by production of hydroxyl radicals. Experimental and theoretical activation energ...
Article
Full-text available
Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds...
Article
Full-text available
Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen. It colonizes different tissues by the utilization of diverse mechanisms. One of these may involve the breakdown of the host cell membrane through the sequential action of hemolytic phospholipase C and phosphorylcholine phosphatase (PchP). The action of hemolytic phospholipase C on p...
Article
Full-text available
The tetrahydroquinoline ring system is a unit found in many biologically active natural products and pharmacologically relevant therapeutic agents. A new series of bistetrahydroquinolines (bis-THQs) was synthesized using imino Diels-Alder reactions between dialdehydes, anilines and N-vinyl-2-pyrrolidone (NVP). The notable features of this procedure...
Article
The interaction of poly(amidoamine)-G3 (PAMAM-G3) dendrimer with nicotinic acid (NA) was investigated by using molecular dynamics (MD) simulations. First, sample free energy profiles of NA crossing PAMAM-G3 at pH 6 and 3 were computed using the adaptive biasing force (ABF) method. We found that PAMAM-G3 provides a more appropriate environment for N...
Article
Full-text available
(E)-2-(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles are described as a new class of selective inhibitors of acetylcholinesterase (AChE). The most potent compound in the series exhibited good AChE inhibitory activity (IC(50) = 64 µM). Compound 7f was found to be more selective than galanthamine in inhibiting AChE and it showed a moderate selecti...
Article
Protein kinases (PKs) are key components of protein phosphorylation based signaling networks in eukaryotic cells. They have been identified as being implicated in many diseases. High-resolution X-ray crystallographic data exist for many PKs and, in many cases, these structures are co-complexed with inhibitors. Although this valuable information con...
Article
Full-text available
The uptake of potassium ions (K+) accompanied by an acidification of the apoplasm is a prerequisite for stomatal opening. The acidification (approximately 2-2.5 pH units) is perceived by voltage-gated inward potassium channels (K(in)) that then can open their pores with lower energy cost. The sensory units for extracellular pH in stomatal K(in) cha...
Article
Semaxanib (SU5416) and 3-[4'-fluorobenzylidene]indolin-2-one (SU5205) are structurally similar drugs that are able to inhibit vascular endothelial growth factor receptor-2 (VEGFR2), but the former is 87 times more effective than the latter. Previously, SU5205 was used as a radiolabelled inhibitor (as surrogate for SU5416) and a radiotracer for posi...
Article
A concise asymmetric diastereoselective strategy for the synthesis of indolo[2,3-a]quinolizidine derivative 1 was developed using diastereoselective addition of 2-siloxyfurans 4 to imine 3 through chiral auxiliary induction. The addition of an ionic liquid as additive in the reaction favored the anti configuration in the major adduct. The stereoche...
Article
N1 substituted pyrazole derivatives show diverse B-Raf kinase inhibitory activities when different hydroxy-substituted cycloalkyl groups are placed at this position. Docking, molecular dynamics (MD) simulations, and hybrid calculation methods (Quantum Mechanics/Molecular Mechanics (QM/MM)) were performed on the complexes, in order to explain these...
Article
Full-text available
We have performed docking of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)aniline (FPTA), 3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)aniline (FPPA), and 4-(4-amino-2-fluorophenoxy)-2-pyridinylamine (AFPP) derivatives complexed with c-Met kinase to study the orientations and preferred active conformations of these inhibitors. The study was con...
Article
Full-text available
Docking and molecular dynamics (MD) simulations of N1 substituted pyrazole derivatives complexed with B-Raf kinase were performed to gain insight into the structural and energetic preferences of these inhibitors. First, a comparative study of fully automated docking programs AutoDock, ICM, GLIDE, and Surflex-Dock in closely approximating the X-ray...
Article
Comparative molecular field analysis (CoMFA) and QM/MM hybrid calculations were performed on 9H-purine derivatives as CDK2 inhibitors. CoMFA was carried out to describe the activities of 78 analogues. The models were applied to a training set including 64 compounds. The best CoMFA model included steric and electrostatic fields, had a good Q(2) valu...
Article
Full-text available
We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated var...