scholarly journals Fast and Accurate Estimation of Gas-Phase Entropy from the Molecular Surface Curvature

2021 ◽  
Author(s):  
Vishwesh Venkatraman ◽  
Amitava Roy
Keyword(s):  
Small Molecules ◽  
Gas Phase ◽  
Rank Order ◽  
Docking Studies ◽  
Molecular Surface ◽  
Accurate Estimation ◽  
Surface Geometry ◽  
Molecular Mechanics Calculations ◽  
Computational Resources ◽  
Speed And Accuracy

Estimating entropy is crucial for understanding and modifying biological systems, such as protein-ligand binding. Current computational methods to estimate entropy require extensive, or at times prohibitively extensive, computational resources. This article presents SHAPE (SHape-based Accurate Predictor of Entropy), a new method that estimates the gas-phase entropy of small molecules purely from their surface geometry. Using SHAPE, the gas-phase entropy of small molecules can be computed in ~ 0.01 CPU hours with run time complexity of Ω(√(Na), where Na is the number of atoms. The accuracy of The method is within 1-2% of computationally expensive quantum mechanical or molecular mechanics calculations. We further show that the inclusion of gas-phase entropy, estimated using SHAPE, improves the rank-order correlation between binding affinity and the binding score from 0.18 to 0.40. The speed and accuracy of SHAPE make it well-suited for use in molecular docking studies as well as in the analysis of structure-activity relationships.

IDENTIFICATION OF SELETIVE CLAUDIN CATION CHANNEL BLOCKERS

2021 ◽  
Vol 27 (Supplement_1) ◽  
pp. S25-S26
Author(s):  
Jingjing Ma ◽  
Emma Wu ◽  
Ye Li ◽  
William Seibel ◽  
Le Shen ◽  
...  
Keyword(s):  
Small Molecules ◽  
Homology Model ◽  
Docking Studies ◽  
Channel Blockers ◽  
Binding Modes ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Dynamics Simulations ◽  
In Silico Models

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that compounds that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative small molecules that bind in the claudin-15 pore. AutoDock Vina was initially used to assess rigid docking using small compound databases. The small molecules were analyzed based on binding affinity to the pore and visualized using VMD for their potential blockage of the channel. Clusters of binding modes were identified based on the prominent interacting residues of the protein with the small molecules. We initially screened 10,500 compounds from within the UIC Centre for Drug Discovery and a cross-section of 10,000 compounds from the NCI open compound repository. This initial screen allowed us to identify 2 first-in-class selective claudin-15 blockers with efficacy in MDCK monolayers induced to express claudin-15 and in wildtype duodenum. Next, we screened the entire NCI open compound repository for additional molecules structurally related to our best initially identified molecule and this has allowed us to identify 13 additional molecules that increase TER of claudin-15 expressing MDCK monolayers by 90–160%. Additionally, these molecules possess similar structural components that will be collected in a fragment library and explored through molecular dynamics simulations. We also developed a claudin-2 homology model on which we are performing docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Our study will provide important insight into the role of claudin-dependent cation permeability in fundamental physiology, which we believe will lead to the utility of claudin blockers as a novel and much needed approach to treat diseases such as IBD.

scholarly journals GENETIC INVOLVEMENT OF INTERLEUKIN 4 FOR ASTHMA AND IDENTIFICATION OF POTENTIAL PHYTOCHEMICAL SCAFFOLD THROUGH MOLECULAR DOCKING STUDIES

2018 ◽  
Vol 10 (1) ◽  
pp. 43 ◽  
Author(s):  
S. Sarithamol ◽  
Divya V. ◽  
Sunitha V. R. ◽  
Suchitra Surendran ◽  
V. L. Pushpa ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Small Molecules ◽  
In Silico ◽  
Mutational Analysis ◽  
Chromosome Region ◽  
Specific Treatment ◽  
Docking Studies ◽  
Interleukin 4 ◽  
Receptor Interaction ◽  
Drug Candidates

Objective: Interleukin 4, an important cytokine, has the major role in the immunomodulatory responses associated with asthma. The present study focused on the involvement of single nucleotide polymorphism variation (SNP) of interleukin 4 (IL4) in the development of disease, asthma and designing small molecules for the inhibition of IL4 through in silico strategy.Methods: Identification of disease causing SNP will be a wise approach towards the phenotype specific treatment. A human origin deleterious no synonymous SNP of IL4 were found out in the chromosome region 5q31-q33 (rs199929962) (T/C). Proteins of the corresponding nucleotide variation were identified and were subjected to characterization studies for selecting the most appropriate one for further mutational analysis and molecular docking studies.Results: Influence of microbes on SNP variation of IL4 gene leading to asthma was found to be insignificant by metagenomic studies. Gene responsive drugs were identified through environmental factor analysis. The drug candidates including corticosteroids were subjected to protein interaction studies by in silico means. The pharmacophoric feature derived from drug receptor interaction was utilized for virtual screening on a dataset of anti-inflammatory phytomolecules. The scaffolds of ellagic acid and quercetin were identified as potential nonsteroidal entities which can shield the asthmatic activities.Conclusion: Developing small molecules using these scaffolds taking interleukin 4 as a target will be an adequate solution for steroid resistant asthma.

Computational UV Spectra for Amorphous Solids of Small Molecules

2021 ◽  
Author(s):  
Austin Michael Wallace ◽  
Ryan C. Fortenberry
Keyword(s):  
Carbon Dioxide ◽  
Interstellar Medium ◽  
Small Molecules ◽  
Gas Phase ◽  
Amorphous Solids ◽  
Uv Spectra ◽  
Ammonia Water ◽  
Gas Phase Molecules ◽  
High Level

Ices in the interstellar medium largely exist as amorphous solids composed of small molecules including ammonia, water, and carbon dioxide. Describing gas-phase molecules can be readily accomplished with current high-level...

Molecular Docking at a Glance

2016 ◽  
pp. 1-38
Author(s):  
Maryam Hamzeh-Mivehroud ◽  
Babak Sokouti ◽  
Siavoush Dastmalchi
Keyword(s):  
Molecular Docking ◽  
Case Studies ◽  
Scientific Community ◽  
Docking Studies ◽  
Search Algorithms ◽  
Steady Increase ◽  
Scoring Functions ◽  
Exponential Expansion ◽  
And Performance ◽  
Computational Resources

The current chapter introduces different aspects of molecular docking technique in order to give an overview to the readers about the topics which will be dealt with throughout this volume. Like many other fields of science, molecular docking studies has experienced a lagging period of slow and steady increase in terms of acquiring attention of scientific community as well as its frequency of application, followed by a pronounced era of exponential expansion in theory, methodology, areas of application and performance due to developments in related technologies such as computational resources and theoretical as well as experimental biophysical methods. In the following sections the evolution of molecular docking will be reviewed and its different components including methods, search algorithms, scoring functions, validation of the methods, and area of applications plus few case studies will be touched briefly.

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