scholarly journals Comprehensive exploration of chemical space using trisubstituted carboranes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yasunobu Asawa ◽  
Saki Hatsuzawa ◽  
Atsushi Yoshimori ◽  
Kentaro Yamada ◽  
Akira Katoh ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Chemical Space ◽  
Hypoxia Inducible Factor ◽  
Pharmacophore Model ◽  
Moment Of Inertia ◽  
Principal Moment ◽  
Virus Activity

AbstractA total of 42 trisubstituted carboranes categorised into five scaffolds were systematically designed and synthesized by exploiting the different reactivities of the twelve vertices of o-, m-, and p-carboranes to cover all directions in chemical space. Significant inhibitors of hypoxia inducible factor transcriptional activitay were mainly observed among scaffold V compounds (e.g., Vi–m, and Vo), whereas anti-rabies virus activity was observed among scaffold V (Va–h), scaffold II (IIb–g), and scaffold IV (IVb) compounds. The pharmacophore model predicted from compounds with scaffold V, which exhibited significant anti-rabies virus activity, agreed well with compounds IIb–g with scaffold II and compound IVb with scaffold IV. Normalized principal moment of inertia analysis indicated that carboranes with scaffolds I–V cover all regions in the chemical space. Furthermore, the first compounds shown to stimulate the proliferation of the rabies virus were found among scaffold V carboranes.

scholarly journals Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-TB Inhibitor Design: A Case Study With Mtb-DapB

2020 ◽  
Vol 8 ◽  
Author(s):  
Chinmayee Choudhury ◽  
Anshu Bhardwaj
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Chemical Space ◽  
Pharmacophore Model ◽  
Model Systems ◽  
Receptor Interaction ◽  
Hybrid Molecules ◽  
Wide Range ◽  
Binding Pockets ◽  
Pharmacophore Models

Antimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200 ns molecular dynamics simulations and trajectories were analyzed to identify stable ligand-receptor interaction features. Based on these interactions, conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 1,563,764 publicly available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4-point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

A Theoretical and Numerical Study of the Dzhanibekov and Tennis Racket Phenomena1

2016 ◽  
Vol 83 (11) ◽  
Author(s):  
Hidenori Murakami ◽  
Oscar Rios ◽  
Thomas Joseph Impelluso
Keyword(s):  
Angular Momentum ◽  
Numerical Study ◽  
The Body ◽  
Moment Of Inertia ◽  
Kutta Method ◽  
Principal Moment ◽  
Tennis Racket ◽  
Angular Momenta ◽  
Runge Kutta Method ◽  
Principal Axes

This paper presents a complete explanation of the Dzhanibekov and the tennis racket phenomena. These phenomena are described by Euler's equation for an unconstrained rigid body that has three distinct moment of inertia values. In the two phenomena, the rotations of a body about the principal axes that correspond to the largest and the smallest moments of inertia are stable. However, the rotation about the axis corresponding to the intermediate principal moment of inertia becomes unstable, leading to the unexpected rotations that are the basis of the phenomena. If this unexpected rotation is not explained from a complete perspective which accounts for the relevant physical and mathematical aspects, one might misconstrue the phenomena as a violation of the conservation of angular momenta. To address this, the phenomenon is investigated using more precise mathematical and graphical tools than those employed previously. The torque-free Euler equations are integrated using the fourth-order Runge–Kutta method. Then, a recovery equation is applied to obtain the rotation matrix for the body. By combining the geometrical solutions with numerical simulations, the unexpected rotations observed in the Dzhanibekov and the tennis racket experiments are shown to preserve the conservation of angular momentum.

scholarly journals Hybrid dynamic pharmacophore models as effective tools to identify novel chemotypes for anti-TB inhibitor design: A case study with Mtb-DapB

2020 ◽  
Author(s):  
Chinmayee Choudhury ◽  
Anshu Bhardwaj
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Chemical Space ◽  
Pharmacophore Model ◽  
Model Systems ◽  
Receptor Interaction ◽  
Hybrid Molecules ◽  
Wide Range ◽  
Binding Pockets ◽  
Pharmacophore Models

AbstractAntimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200ns molecular dynamics simulations and trajectories were analyzed to identify stable ligand-receptor interaction features. Based on these interactions, conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 15, 63,764 publicly available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4-point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

scholarly journals Non–Linear Analysis of Slender Masonry Beam

2017 ◽  
Vol 17 (2) ◽  
pp. 151-160 ◽  
Author(s):  
Marek Vokál ◽  
Michal Drahorád
Keyword(s):  
Numerical Analysis ◽  
Axial Force ◽  
Mathematical Theory ◽  
Bending Moment ◽  
Linear Analysis ◽  
Moment Of Inertia ◽  
Principal Moment ◽  
Analysis And Design ◽  
Non Linear ◽  
Slender Columns

Abstract This paper deals with numerical analysis and design of slander prismatic masonry beams loaded predominantly by axial force and bending moment in plane of the principal moment of inertia. Because of the material non-linearity, classical mathematical theory of slender columns cannot be applied for masonry elements, therefore the proposed method uses iterative non–linear calculation considering both material and geometrical non–linearity.

scholarly journals Hybrid Dynamic Pharmacophore Models as Effective Tools to Identify Novel Chemotypes for Anti-tb Inhibitor Design: a Case Study With Mtb-dapb

2020 ◽  
Author(s):  
Chinmayee Choudhury ◽  
Anshu Bhardwaj
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Chemical Space ◽  
Pharmacophore Model ◽  
Model Systems ◽  
Receptor Interaction ◽  
Hybrid Molecules ◽  
Wide Range ◽  
Binding Pockets ◽  
Pharmacophore Models

Abstract Antimicrobial resistance (AMR) is one of the most serious global public health threats as it compromises the successful treatment of deadly infectious diseases like tuberculosis. New therapeutics are constantly needed but it takes a long time and is expensive to explore new biochemical space. One way to address this issue is to repurpose the validated targets and identify novel chemotypes that can simultaneously bind to multiple binding pockets of these targets as a new lead generation strategy. This study reports such a strategy, dynamic hybrid pharmacophore model (DHPM), which represents the combined interaction features of different binding pockets contrary to the conventional approaches, where pharmacophore models are generated from single binding sites. We have considered Mtb-DapB, a validated mycobacterial drug target, as our model system to explore the effectiveness of DHPMs to screen novel unexplored compounds. Mtb-DapB has a cofactor binding site (CBS) and an adjacent substrate binding site (SBS). Four different model systems of Mtb-DapB were designed where, either NADPH/NADH occupies CBS in presence/absence of an inhibitor 2, 6-PDC in the adjacent SBS. Two more model systems were designed, where 2, 6-PDC was linked to NADPH and NADH to form hybrid molecules. The six model systems were subjected to 200ns molecular dynamics simulations and trajectories were analysed to identify stable ligand-receptor interaction features. Based on these interactions, Conventional pharmacophore models (CPM) were generated from the individual binding sites while DHPMs were created from hybrid-molecules occupying both binding sites. A huge library of 15, 63,764 publically available molecules were screened by CPMs and DHPMs. The screened hits obtained from both types of models were compared based on their Hashed binary molecular fingerprints and 4 point pharmacophore fingerprints using Tanimoto, Cosine, Dice and Tversky similarity matrices. Molecules screened by DHPM exhibited significant structural diversity, better binding strength and drug like properties as compared to the compounds screened by CPMs and the reported anti-mycobacterial molecules indicating the efficiency of DHPM to explore new chemical space for anti-TB drug discovery. The idea of DHPM can be applied for a wide range of mycobacterial or other pathogen targets to venture into unexplored chemical space.

scholarly journals Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches

Molecules ◽  
2019 ◽  
Vol 24 (20) ◽  
pp. 3641 ◽  
Author(s):  
Szilágyi ◽  
Hajdú ◽  
Flachner ◽  
Lőrincz ◽  
Balczer ◽  
...  
Keyword(s):  
Virtual Screening ◽  
In Silico ◽  
Serine Proteases ◽  
Chemical Space ◽  
Early Stage ◽  
3D Structure ◽  
Pharmacophore Model ◽  
Biological Assays ◽  
Molecule Inhibitor

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade. Designing C1 inhibitors is particularly challenging since known inhibitors are restricted to a narrow bioactive chemical space in addition selectivity over other serine proteases is an important requirement. The typical architecture of a small molecule inhibitor of C1s contains an amidine (or guanidine) residue, however, the discovery of non-amidine inhibitors might have high value, particularly if novel chemotypes and/or compounds displaying improved selectivity are identified. We applied various virtual screening approaches to identify C1s focused libraries that lack the amidine/guanidine functionalities, then the in silico generated libraries were evaluated by in vitro biological assays. While 3D structure-based methods were not suitable for virtual screening of C1s inhibitors, and a 2D similarity search did not lead to novel chemotypes, pharmacophore model generation allowed us to identify two novel chemotypes with submicromolar activities. In three screening rounds we tested altogether 89 compounds and identified 20 hit compounds (<10 μM activities; overall hit rate: 22.5%). The highest activity determined was 12 nM (1,2,4-triazole), while for the newly identified chemotypes (1,3-benzoxazin-4-one and thieno[2,3-d][1,3]oxazin-4-one) it was 241 nM and 549 nM, respectively.

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