scholarly journals Intramolecular interactions enhance the potency of gallinamide A analogs against Trypanosoma cruzi

2021 ◽  
Author(s):  
Elany Barbosa Da Silva ◽  
Vandna Sharma ◽  
Lilian Hernandez-Alvarez ◽  
Arthur H Tang ◽  
Alexander Stoye ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Drug Target ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Intramolecular Interactions ◽  
Bioactive Conformation ◽  
Synthetic Analogs ◽  
C Terminus ◽  
Target Binding ◽  
Dynamics Simulations

Gallinamide A, a metabolite of the marine cyanobacterium Schizothrix sp., selectively inhibits cathepsin L-like cysteine proteases. We evaluated potency of gallinamide A and 23 synthetic analogs against intracellular Trypanosoma cruzi amastigotes and the cysteine protease, cruzain. We determined the co-crystal structures of cruzain with gallinamide A and two synthetic analogs at ~2Å. SAR data revealed that the N-terminal end of gallinamide A is loosely bound and weakly contributes in drug-target interactions. At the C-terminus, the intramolecular π-π stacking interactions between the aromatic substituents at P1 ′ and P1 restrict the bioactive conformation of the inhibitors, thus minimizing the entropic loss associated with target binding. Molecular dynamics simulations showed that in the absence of an aromatic group at P1, the substituent at P1′ interacts with tryptophan-184. The P1-P1′ interactions had no effect on anti-cruzain activity whereas anti-T. cruzi potency increased by ~5-fold, likely due to an increase in solubility/permeability of the analogs.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

scholarly journals Allosteric activation of SENP1 by SUMO1 β-grasp domain involves a dock-and-coalesce mechanism

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Jingjing Guo ◽  
Huan-Xiang Zhou
Keyword(s):  
Cysteine Proteases ◽  
Distal Portion ◽  
Distal Region ◽  
Dynamic Changes ◽  
Catalytic Center ◽  
Cellular Processes ◽  
Correlated Motions ◽  
C Terminus ◽  
Nanosecond Dynamics ◽  
Dynamics Simulations

Small ubiquitin-related modifiers (SUMOs) are conjugated to proteins to regulate a variety of cellular processes. SENPs are cysteine proteases with a catalytic center located within a channel between two subdomains that catalyzes SUMO C-terminal cleavage for processing of SUMO precursors and de-SUMOylation of target proteins. The β-grasp domain of SUMOs binds to an exosite cleft, and allosterically activates SENPs via an unknown mechanism. Our molecular dynamics simulations showed that binding of the β-grasp domain induces significant conformational and dynamic changes in SENP1, including widening of the exosite cleft and quenching of nanosecond dynamics in all but a distal region. A dock-and-coalesce mechanism emerges for SENP-catalyzed SUMO cleavage: the wedging of the β-grasp domain enables the docking of the proximal portion of the C-terminus and the strengthened cross-channel motional coupling initiates inter-subdomain correlated motions to allow for the distal portion to coalesce around the catalytic center.

scholarly journals Design of Gallinamide A Analogs as Potent Inhibitors of the Cysteine Proteases Human Cathepsin L and Trypanosoma cruzi Cruzain

2019 ◽  
Vol 62 (20) ◽  
pp. 9026-9044 ◽  
Author(s):  
Paul D. Boudreau ◽  
Bailey W. Miller ◽  
Laura-Isobel McCall ◽  
Jehad Almaliti ◽  
Raphael Reher ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Cathepsin L ◽  
Cysteine Proteases ◽  
Human Cathepsin

scholarly journals All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

2021 ◽  
Author(s):  
Carolina Pérez Segura ◽  
Boon Chong Goh ◽  
Jodi A. Hadden-Perilla
Keyword(s):  
Small Molecules ◽  
Drug Target ◽  
Structural Changes ◽  
Salt Bridge ◽  
Md Simulations ◽  
Health Concern ◽  
Protein Dimer ◽  
B Virus ◽  
Flexible Protein ◽  
Dynamics Simulations

AbstractThe hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important anti-viral paradigm based on disrupting the timing of genome encapsulation. Crystallographic studies of AT130-bound complexes have been essential in explaining the effects of the small molecule on HBV capsid structure; however, computational examination reveals that key changes attributed to AT130 were erroneous, likely a consequence of interpreting poor resolution arising from a highly flexible protein. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that, rather than damaging spike helicity, AT130 enhances the capsid’s ability to recover it. A new conformational state is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these domains. Combined with dynamical network analysis, results describe a connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire capsid protein dimer.

scholarly journals Residue-Level Contact Reveals Modular Domain Interactions of PICK1 Are Driven by Both Electrostatic and Hydrophobic Forces

2021 ◽  
Vol 7 ◽  
Author(s):  
Amy O. Stevens ◽  
Yi He
Keyword(s):  
Hydrophobic Interactions ◽  
Pdz Domain ◽  
Md Simulations ◽  
Intramolecular Interactions ◽  
Coarse Grained ◽  
Scaffolding Protein ◽  
Concave Surface ◽  
Stable Complex ◽  
Bar Domain ◽  
C Terminus

PICK1 is a multi-domain scaffolding protein that is uniquely comprised of both a PDZ domain and a BAR domain. While previous experiments have shown that the PDZ domain and the linker positively regulate the BAR domain and the C-terminus negatively regulates the BAR domain, the details of internal regulation mechanisms are unknown. Molecular dynamics (MD) simulations have been proven to be a useful tool in revealing the intramolecular interactions at atomic-level resolution. PICK1 performs its biological functions in a dimeric form which is extremely computationally demanding to simulate with an all-atom force field. Here, we use coarse-grained MD simulations to expose the key residues and driving forces in the internal regulations of PICK1. While the PDZ and BAR domains do not form a stable complex, our simulations show the PDZ domain preferentially interacting with the concave surface of the BAR domain over other BAR domain regions. Furthermore, our simulations show that the short helix in the linker region can form interactions with the PDZ domain. Our results reveal that the surface of the βB-βC loop, βC strand, and αA-βD loop of the PDZ domain can form a group of hydrophobic interactions surrounding the linker helix. These interactions are driven by hydrophobic forces. In contrast, our simulations reveal a very dynamic C-terminus that most often resides on the convex surface of the BAR domain rather than the previously suspected concave surface. These interactions are driven by a combination of electrostatic and hydrophobic interactions.

scholarly journals Molecular Characterization of a Novel Cathepsin L in Macrobrachium nipponense and Its Function in Ovary Maturation

2022 ◽  
Vol 12 ◽  
Author(s):  
Sufei Jiang ◽  
Yiwei Xiong ◽  
Wenyi Zhang ◽  
Junpeng Zhu ◽  
Dan Cheng ◽  
...  
Keyword(s):  
Cathepsin L ◽  
Cysteine Proteases ◽  
Macrobrachium Nipponense ◽  
Reading Frame ◽  
Physiological Processes ◽  
Gonad Somatic Index ◽  
Oriental River Prawn ◽  
Ovary Maturation

Cathepsin L genes, which belonged to cysteine proteases, were a series of multifunctional protease and played important roles in a lot of pathological and physiological processes. In this study, we analyzed the characteristics a cathepsin L (named Mn-CL2) in the female oriental river prawn, Macrobrachium nipponense which was involved in ovary maturation. The Mn-CL2 was1,582 bp in length, including a 978 bp open reading frame that encoded 326 amino acids. The Mn-CL2 was classified into the cathepsin L group by phylogenetic analysis. Real-time PCR (qPCR) analysis indicated that Mn-CL2 was highly expressed in the hepatopancreas and ovaries of female prawns. During the different ovarian stages, Mn-CL2 expression in the hepatopancreas and ovaries peaked before ovarian maturation. In situ hybridization studies revealed that Mn-CL2 was localized in the oocyte of the ovary. Injection of Mn-CL2 dsRNA significantly reduced the expression of vitellogenin. Changes in the gonad somatic index also confirmed the inhibitory effects of Mn-CL2 dsRNA on ovary maturation. These results suggest that Mn-CL2 has a key role in promoting ovary maturation.

scholarly journals Structure and Vitamin D₃-Binding Affinity of Milk Proteins

2021 ◽  
Author(s):  
Muhammad Ali Naqvi
Keyword(s):  
Vitamin D ◽  
Milk Proteins ◽  
Sodium Caseinate ◽  
Intramolecular Interactions ◽  
Radius Of Gyration ◽  
Casein Micelle ◽  
Casein Phosphopeptide ◽  
Dynamics Simulations ◽  
Binding Mechanisms ◽  
Good Agreement

Two projects formed the basis of this thesis related to protein-vitamin D₃ (VD₃) binding mechanisms and efficacy. First, a method to characterize the binding of VD₃ to food-related macromolecules that may be used for enrichment of milk was devised. Results suggested that sodium caseinate and hydroxylpropyl-β-cyclodextrin could effectively bind VD₃ and may be used as carriers. Secondly, molecular dynamics simulations were used to determine the conformation ensemble of the β-casein phosphopeptide (β-CPP). Radius of gyration, H-bonding, Ramachandran plot, and secondary structure were ascertained, and showed good agreement with simulations of other disordered pepitides as well as experimental data of β-CPP. Overall, this new binding assay now affords the ability to study interactions between macromolecules and vitamin D₃. As well, by performing simulations of a single casein peptide, important data needed to understand the intramolecular interactions and structure of β-casein (as well as the casein micelle) have be elucidated.

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