scholarly journals Computer-Aided Design of Peptidomimetic Inhibitors of Falcipain-3: QSAR and Pharmacophore Models

2021 ◽  
Vol 89 (4) ◽  
pp. 44
Author(s):  
Boris D. Bekono ◽  
Akori E. Esmel ◽  
Brice Dali ◽  
Fidele Ntie-Kang ◽  
Melalie Keita ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
Molecular Design ◽  
Structural Information ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
Combinatorial Libraries ◽  
3D Qsar ◽  
3D Models ◽  
Qsar Model ◽  
Computer Aided

In this work, antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) are proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities () were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure–activity relationships (QSAR) model based on a linear correlation between computed GFE () and the experimentally measured . Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogues where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictive inhibitory activities falling within the low nanomolar concentration range.

scholarly journals Computer-aided Design of Peptidomimetic Inhibitors of falcipain-3: QSAR and Pharmacophore Models

2021 ◽  
Author(s):  
Boris D. Bekono ◽  
Akori Esmel ◽  
Brice Dali ◽  
Fidele Ntie-Kang ◽  
Melalie Keita ◽  
...  
Keyword(s):  
Computer Aided Design ◽  
Molecular Design ◽  
Structural Information ◽  
Three Dimensional ◽  
Pharmacophore Model ◽  
Combinatorial Libraries ◽  
3D Qsar ◽  
3D Models ◽  
Qsar Model ◽  
Computer Aided

In this work antiparasitic peptidomimetics inhibitors (PEP) of falcipain-3 (FP3) of Plasmodium falciparum (Pf) have been proposed using structure-based and computer-aided molecular design. Beginning with the crystal structure of PfFP3-K11017 complex (PDB ID: 3BWK), three-dimensional (3D) models of FP3-PEPx complexes with known activities (IC50exp) were prepared by in situ modification, based on molecular mechanics and implicit solvation to compute Gibbs free energies (GFE) of inhibitor-FP3 complex formation. This resulted in a quantitative structure-activity relationships (QSAR) model based on a linear correlation between computed GFE (ΔΔGcomp) and the experimentally measured IC50exp: (pIC50exp=-(IC50exp/109) =-0.4517×∆∆Gcomp+4.0865 ; R2 = 0.89). Apart from the structure-based relationship, a ligand-based quantitative pharmacophore model (PH4) of novel PEP analogs where substitutions were directed by comparative analysis of the active site interactions was derived using the proposed bound conformations of the PEPx. This provided structural information useful for the design of virtual combinatorial libraries (VL), which was virtually screened based on the 3D-QSAR PH4. The end results were predictory inhibitory activities falling within the low nanomolar concentration range.

scholarly journals Design of Thymidine Analogues Targeting Thymidilate Kinase ofMycobacterium tuberculosis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Luc Calvin Owono Owono ◽  
Melalie Keita ◽  
Eugene Megnassan ◽  
Vladimir Frecer ◽  
Stanislav Miertus
Keyword(s):  
Free Energy ◽  
Molecular Modeling ◽  
Molecular Design ◽  
Structural Information ◽  
3D Qsar ◽  
3D Models ◽  
Pyrimidine Ring ◽  
Qsar Model ◽  
Active Site Residues ◽  
Pharmacophore Generation

We design here new nanomolar antituberculotics, inhibitors ofMycobacterium tuberculosisthymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmtcocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔGcom) andKivalues explains 94% of the TMPKmtinhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94) by variation of the computedΔΔGcomand 92% for the pharmacophore (PH4) model (pKi=1.0206×pKipred-0.0832,  R2=0.92). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predictedKiof 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.

scholarly journals Conformational analysis and molecular design of anthranilic acid derivatives as partial agonists of the Farnesoid X Receptor (FXR) with favorable predicted pharmacokinetic profiles

2021 ◽  
Vol 5 (2) ◽  
pp. 585-600
Author(s):  
Guy Müller Banquet OKRA ◽  
◽  
Dali Brice ◽  
Hermann N'Guessan ◽  
Affiba Florance Kouassi ◽  
...  
Keyword(s):  
Anthranilic Acid ◽  
Molecular Design ◽  
Pharmacophore Model ◽  
3D Qsar ◽  
Qsar Model ◽  
Farnesoid X Receptor ◽  
Virtual Design ◽  
Ligand Complex ◽  
Pharmacokinetic Profiles ◽  
Anthranilic Acid Derivatives

We report here virtual design of new anthranilic acid derivatives (AAD) identified as potent partial Farnesoid X recep-tor (FXR) agonists with favorable predicted pharmacokinetic profiles. By in situ modification of the crystal structure (PDB ID: 3OLF) of FXR complex with a benzimidazole-based partial agonistic ligand, 3D models of 17 FXR:AADx complexes with known observed activity (EC50exp) were prepared to establish a quantitative structure–activity (QSAR) model and linear correla-tion between relative Gibbs free energy (GFE) of receptor-ligand complex formation (Gcom) and EC50exp: pEC50exp = -0,1146 Gcom + 8,175 (#); R2 = 0.98. A 3D QSAR pharmacophore model (PH4) derived from the QSAR directed our effort to design novel AAD analogs. During the design, an initial virtual library of 94501 AAD was focused down to 33134 drug-like compounds and finally, PH4 screened to identify 100 promising compounds. Theoretical EC50 (EC50pre) values of all analogs compounds were predicted by means of equation (#) and their pharmacokinetics (ADME) profiles were computed. More than 12 putative AADs display EC50pre 300 times superior to that of the reported most active training set inhibitor AAD1.

CoMFA, CoMSIA and HQSAR Analysis of 3-aryl-3-ethoxypropanoic Acid Derivatives as GPR40 Modulators

2020 ◽  
Vol 17 (1) ◽  
pp. 100-118
Author(s):  
Krishna A. Gajjar ◽  
Anuradha K. Gajjar
Keyword(s):  
Biological Activity ◽  
Structural Information ◽  
Three Dimensional ◽  
3D Qsar ◽  
Qsar Model ◽  
Quantitative Structure Activity Relationship ◽  
Docking Studies ◽  
Statistical Parameters ◽  
Qsar Study ◽  
Negative Contribution

Background: Human GPR40 receptor, also known as free fatty-acid receptor 1, is a Gprotein- coupled receptor that binds long chain free fatty acids to enhance glucose-dependent insulin secretion. In order to improve the resistance and efficacy, computational tools were applied to a series of 3-aryl-3-ethoxypropanoic acid derivatives. A relationship between the structure and biological activity of these compounds, was derived using a three-dimensional quantitative structure-activity relationship (3D-QSAR) study using CoMFA, CoMSIA and two-dimensional QSAR study using HQSAR methods. Methods: Building the 3D-QSAR models, CoMFA, CoMSIA and HQSAR were performed using Sybyl-X software. The ratio of training to test set was kept 70:30. For the generation of 3D-QSAR model three different alignments were used namely, distill, pharmacophore and docking based alignments. Molecular docking studies were carried out on designed molecules using the same software. Results: Among all the three methods used, Distill alignment was found to be reliable and predictive with good statistical results. The results obtained from CoMFA analysis q2, r2cv and r2 pred were 0.693, 0.69 and 0.992 respectively and in CoMSIA analysis q2, r2cv and r2pred were 0.668, 0.648 and 0.990. Contour maps of CoMFA (lipophilic and electrostatic), CoMSIA (lipophilic, electrostatic, hydrophobic, and donor) and HQSAR (positive & negative contribution) provided significant insights i.e. favoured and disfavoured regions or positive & negative contributing fragments with R1 and R2 substitutions, which gave hints for the modifications required to design new molecules with improved biological activity. Conclusion: 3D-QSAR techniques were applied for the first time on the series 3-aryl-3- ethoxypropanoic acids. All the models (CoMFA, CoMSIA and HQSAR) were found to be satisfactory according to the statistical parameters. Therefore such a methodology, whereby maximum structural information (from ligand and biological target) is explored, gives maximum insights into the plausible protein-ligand interactions and is more likely to provide potential lead candidates has been exemplified from this study.

scholarly journals Penguatan kompetensi perancangan mesin melalui pelatihan computer-aided design bagi mahasiswa dan alumni teknik mesin (Strengthening of machine design skills through the computer-aided design training for mechanical engineering students and alumni)

2021 ◽  
Vol 1 (2) ◽  
pp. 44-49
Author(s):  
I Irwansyah ◽  
Asbar Asbar ◽  
Amir Zaki Mubarak
Keyword(s):  
Computer Aided Design ◽  
Three Dimensional ◽  
3D Models ◽  
International Organization ◽  
Machine Design ◽  
Two Dimensional ◽  
Design Task ◽  
International Organization For Standardization ◽  
Computer Aided ◽  
Aided Design

ABSTRAKTujuan dilaksanakan pengabdian ini untuk memperkenalkan dan memberikan pelatihan penggunaan perangkat lunak Autodesk Inventor untuk memproduksi gambar teknik berbasis Computer-aided Design (CAD) menurut International Organization for Standardization (ISO). Metode yang dilaksanakan melalui teori, praktik dan diskusi serta penyelesaian tugas perancangan mesin secara mandiri dan berkelompok. Materi pelatihan meliputi gambar kerja, pengenalan dasar CAD, pemodelan gambar two-dimensional (2D) dan three-dimensional (3D), perakitan dan presentasi model 3D. Evaluasi kegiatan dinilai mengacu pada kesiapan penyelesaian tugas perancangan dan kesesuaian hasil gambar menurut standar ISO. Berdasarkan hasil pelatihan CAD tingkat dasar diperoleh capaian dimana peserta telah menyelesaikan materi pembekalan menggambar teknik dan berhasil menyelesaikan tugas perancangan yang diberikan. Tugas proyek perancangan yang diberikan menuntut penguasaan dalam hal membuat model 3D dari gambar sketsa 2D, membuat gambar susunan, membuat gambar kerja dan menyajikannya dalam format presentasi model bergerak. Keberhasilan menyelesaikan tugas tersebut mengindikasikan bahwa para peserta paham dan mampu mengoperasikan perangkat lunak Autodesk Inventor. Kesimpulan, kemampuan dasar ini dapat dijadikan bekal untuk pengembangan diri peserta dalam pengembangan dan penguasaan CAD tingkat lanjut. Kegiatan ini memberikan kontribusi berdasarkan tingginya animo untuk mengikuti pelatihan hingga akhir dan menyelesaikan tugas, dan juga memberikan dampak secara tidak langsung kepada persiapan tenaga terampil CAD pada industri di Aceh.Kata kunci: perancangan berbantuan komputer; gambar teknik 2D/3D; Autodesk InventorABSTRACTThe purpose of this service is to introduce and provide training on the use of Autodesk Inventor software to produce Computer-aided Design (CAD) based technical drawings according to the International Organization for Standardization (ISO). The method is carried out through theory, practice, and discussion, as well as completing machine design tasks independently and in groups. The training materials include working drawings, basic introduction to CAD, two-dimensional (2D) and three-dimensional (3D) drawing modeling, assembly, and presentation of 3D models. Evaluation of activities assessed refers to the readiness to complete the design task and the suitability of the drawings according to ISO standards. Based on the results of the basic level CAD training, there were achievements where participants had completed the technical drawing briefing material and completed the given design task. The design project task given requires mastery in terms of making 3D models from 2D sketch images, making layout drawings, making working drawings, and presenting them in a moving model presentation format. Successful completion of the task indicates that the participants understand and can operate the Autodesk Inventor software. In conclusion, this basic ability can be used as a provision for participants' self-development in the development and mastery of advanced CAD. This activity contributes based on the high interest in participating in training to the end and completing assignments and also has an indirect impact on the preparation of skilled CAD workers in the industry in Aceh.Keywords: computer-aided design; 2D/3D engineering drawing; Autodesk Inventor

scholarly journals Assessment of Differences in the Dimensions of Mandible Condyle Models in Fan- versus Cone-Beam Computer Tomography Acquisition

Materials ◽  
2021 ◽  
Vol 14 (6) ◽  
pp. 1388
Author(s):  
Bartosz Bielecki-Kowalski ◽  
Marcin Kozakiewicz
Keyword(s):  
Computer Tomography ◽  
Computer Aided Design ◽  
Three Dimensional ◽  
Daily Practice ◽  
Neck Surgery ◽  
3D Models ◽  
Cone Beam ◽  
Computer Aided ◽  
Mandible Condyle ◽  
Cone Beam Computer Tomography

Modern treatment in the field of head and neck surgery aims for the least invasive therapy and places great emphasis on restorative treatment, especially in the case of injury and deformation corrective surgery. More and more often, surgeons use CAD/CAM (Computer-Aided Design and Computer-Aided Manufacturing) tools in their daily practice in the form of models, templates, and computer simulations of planning. These tools are based on DICOM (Digital Imaging and Communications in Medicine) files derived from computed tomography. They can be obtained from both fan-beam (FBCT) and cone-beam tomography (CBCT) acquisitions, which are subsequently segmented in order to transform them into a 1-bit 3D model, which is the basis for further CAD processes. Aim: Evaluation of differences in the dimensions of mandible condyle models in fan- versus cone-beam computer tomography for surgical treatment purposes. Methods: 499 healthy condyles were examined in CT-based 3D models of Caucasians aged 8–88 years old. Datasets were obtained from 66 CBCT and 184 FBCT axial image series (in each case, imaging both mandible condyles resulted in the acquisition of 132 condyles from CBCT and 368 condyles from FBCT) and were transformed into three-dimensional models by digital segmentation. Eleven different measurements were performed to obtain information whether there were any differences between FBCT and CBCT models of the same anatomical region. Results: 7 of 11 dimensions were significantly higher in FBCT versus lower in CBCT (p < 0.05).

scholarly journals Automatized Evaluation of Students’ CAD Models

2021 ◽  
Vol 11 (4) ◽  
pp. 145
Author(s):  
Nenad Bojcetic ◽  
Filip Valjak ◽  
Dragan Zezelj ◽  
Tomislav Martinec
Keyword(s):  
Computer Aided Design ◽  
Three Dimensional ◽  
Computer Application ◽  
Test Cases ◽  
Cad Model ◽  
Computer Solution ◽  
3D Cad ◽  
Computer Aided ◽  
Cad Models ◽  
Aided Design

The article describes an attempt to address the automatized evaluation of student three-dimensional (3D) computer-aided design (CAD) models. The driving idea was conceptualized under the restraints of the COVID pandemic, driven by the problem of evaluating a large number of student 3D CAD models. The described computer solution can be implemented using any CAD computer application that supports customization. Test cases showed that the proposed solution was valid and could be used to evaluate many students’ 3D CAD models. The computer solution can also be used to help students to better understand how to create a 3D CAD model, thereby complying with the requirements of particular teachers.

Determination of the Workspace of a Three-Degrees-of-Freedom Parallel Manipulator Using a Three-Dimensional Computer-Aided-Design Software Package and the Concept of Virtual Chains1

2015 ◽  
Vol 8 (2) ◽  
Author(s):  
Andrew Johnson ◽  
Xianwen Kong ◽  
James Ritchie
Keyword(s):  
Computer Aided Design ◽  
Parallel Manipulator ◽  
Degrees Of Freedom ◽  
Graphical Representation ◽  
Three Dimensional ◽  
Parallel Manipulators ◽  
Workspace Analysis ◽  
Computer Aided ◽  
Aided Design

The determination of workspace is an essential step in the development of parallel manipulators. By extending the virtual-chain (VC) approach to the type synthesis of parallel manipulators, this technical brief proposes a VC approach to the workspace analysis of parallel manipulators. This method is first outlined before being illustrated by the production of a three-dimensional (3D) computer-aided-design (CAD) model of a 3-RPS parallel manipulator and evaluating it for the workspace of the manipulator. Here, R, P and S denote revolute, prismatic and spherical joints respectively. The VC represents the motion capability of moving platform of a manipulator and is shown to be very useful in the production of a graphical representation of the workspace. Using this approach, the link interferences and certain transmission indices can be easily taken into consideration in determining the workspace of a parallel manipulator.

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