“MedChemVR”: A Virtual Reality Game to Enhance Medicinal Chemistry Education

Medicinal chemistry (MC) is an indispensable component of the pharmacy curriculum. The pharmacists’ unique knowledge of a medicine’s chemistry enhances their understanding of the pharmacological activity, manufacturing, storage, use, supply, and handling of drugs. However, chemistry is a challenging subject for both teaching and learning. These challenges are typically caused by the inability of students to construct a mental image of the three-dimensional (3D) structure of a drug molecule from its two-dimensional presentations. This study explores a prototype virtual reality (VR) gamification option, as an educational tool developed to aid the learning process and to improve the delivery of the MC subject to students. The developed system is evaluated by a cohort of 41 students. The analysis of the results was encouraging and provided invaluable feedback for the future development of the proposed system

Identifying the Characteristics of Virtual Reality Gamification for Complex Educational Topics

Multidisciplinary topics in education pose a major challenge for traditional learning and teaching methods. Such topics can deter students from selecting particular courses or hinder their study progress. This study focused on the subject of medicinal chemistry, which is a discipline combining medicine and chemistry. This combination of applied and basic science creates a complex field of education that is challenging to both teach and learn. Chemical and pharmacological principles are typically presented in 2D molecular structures and, recently, 3D molecular models have been utilized to improve the visualization of chemical compounds and their chemical interactions. Contemporary studies have presented Virtual Reality (VR) as an alternative method for improving the learning and teaching of multidisciplinary specialties such as this. However, current educational efforts employing VR offer limited interactivity and a traditional teaching method previously presented in 2D. This reduces students’ interest and concentration in the taught subjects. This paper presents the development rationale of a novel VR educational application based on the evaluation of the user requirements by 405 pharmacy undergraduate students. The results informed the development and preliminary evaluation of a proposed VR serious game application, which was deployed in a real-life class environment and evaluated in contrast to traditional teaching methods by 15 students. The derived results confirmed the advantages of VR technology as a learning and teaching tool, in addition to the end-users’ willingness to adopt VR systems as a learning aid

Identifying the Characteristics of Virtual Reality Gamification for Complex Educational Topics

Multidisciplinary topics in education pose a major challenge for traditional learning and teaching methods. Such topics can deter students from selecting particular courses or hinder their study progress. This study focused on the subject of medicinal chemistry, which is a discipline combining medicine and chemistry. This combination of applied and basic science creates a complex field of education that is challenging to both teach and learn. Chemical and pharmacological principles are typically presented in 2D molecular structures and, recently, 3D molecular models have been utilized to improve the visualization of chemical compounds and their chemical interactions. Contemporary studies have presented Virtual Reality (VR) as an alternative method for improving the learning and teaching of multidisciplinary specialties such as this. However, current educational efforts employing VR offer limited interactivity and a traditional teaching method previously presented in 2D. This reduces students’ interest and concentration in the taught subjects. This paper presents the development rationale of a novel VR educational application based on the evaluation of the user requirements by 405 pharmacy undergraduate students. The results informed the development and preliminary evaluation of a proposed VR serious game application, which was deployed in a real-life class environment and evaluated in contrast to traditional teaching methods by 15 students. The derived results confirmed the advantages of VR technology as a learning and teaching tool, in addition to the end-users’ willingness to adopt VR systems as a learning aid

Arylamine N-Acetyltransferases from mycobacteria: investigations of a potential yarget for anti-tubercular therapy

Reactivation of latent infection is the major cause of tuberculosis (TB). Cholesterol is a critical carbon source during latent infection. Catabolism of cholesterol contributes to the pool of propionyl-CoA, a precursor that is incorporated into cell-wall lipids. Arylamine N-acetyltransferase (NAT) is encoded within a gene cluster that is involved in the sterol-ring degradation and is essential for intracellular survival. NAT from M. tuberculosis (TBNAT) can utilise propionyl-CoA and therefore was proposed as a target for TB-drug development. Deleting the nat gene or inhibiting the NAT enzyme prevents intracellular survival and results in depletion of cell-wall lipids. NAT inhibitors, including the piperidinol class, were identified by high-throughput screening. The insolubility of recombinant TBNAT has been a major limitation in pursuing it as a drug target. Subcloning tbnat into a pVLT31 vector resulted in a yield of 6-16 mg/litre-bacterial-culture of pure-soluble recombinant TBNAT. The increased yield allowed for extensive screening for crystallisation conditions. However, since a structure was not obtained, the model NAT from M. marinum (MMNAT) was employed to further understand NAT as a target. Screening against a panel of Acyl-CoA cofactors showed that MMNAT can also utilise propionyl-CoA. The MMNAT structure in complex with the high affinity substrate hydralazine was determined (2.1 Å) and the architecture of the arylamine pocket was delineated. A novel mechanism for the acetylation reaction of hydralazine has emerged. It is proposed that the acetyl group is transferred from acetyl-CoA to the heterocyclic aromatic nitrogen of hydralazine, which explains the immediate cyclisation of the acetylated metabolite into an N-methyltriazolophthalazine. By employing mass spectroscopy, enzyme assays, computational docking and structural studies, a covalent mechanism of inhibition by the piperidinol class was established, and the inhibitor-binding pocket was identified. Inhibitors with new scaffolds were identified using the in silico 3D-shape screening and thermal shift assay.</p

Comparison of the Arylamine N-acetyltransferase from Mycobacterium marinum and Mycobacterium tuberculosis

Arylamine N-acetyltansferase (NAT) from Mycobacterium tuberculosis (TBNAT) is a potential drug target for anti-tubercular therapy. Recombinant TBNAT is much less soluble and is produced in lower yields than the closely related NAT from Mycobacterium marinum (MMNAT). In order to explore MMNAT as a model for TBNAT in drug discovery, we compare the two mycobacterial NAT enzymes. Two site-directed mutants of MMNAT have been prepared and characterised: MMNAT71, Tyr --> Phe and MMNAT209, Met --> Thr, in which residues within 6 A of the active-site cysteine have been replaced with the corresponding residue from TBNAT. Two chimeric proteins have also been produced in which the third domain of MMNAT has been replaced by the third domain of TBNAT and vice versa. The activity profile of the chimeric proteins suggests a role for the third domain in the evolutionary divergence of NAT between these closely related mycobacterial species

Probing the architecture of the Mycobacterium marinum arylamine N-acetyltransferase active site

Treatment of latent tuberculosis infection remains an important goal of global TB eradication. To this end, targets that are essential for intracellular survival of Mycobacterium tuberculosis are particularly attractive. Arylamine N-acetyltransferase (NAT) represents such a target as it is, along with the enzymes encoded by the associated gene cluster, essential for mycobacterial survival inside macrophages and involved in cholesterol degradation. Cholesterol is likely to be the fuel for M. tuberculosis inside macrophages. Deleting the nat gene and inhibiting the NAT enzyme prevents survival of the microorganism in macrophages and induces cell wall alterations, rendering the mycobacterium sensitive to antibiotics to which it is normally resistant. To date, NAT from M. marinum (MMNAT) is considered the best available model for NAT from M. tuberculosis (TBNAT). The enzyme catalyses the acetylation and propionylation of arylamines and hydrazines. Hydralazine is a good acetyl and propionyl acceptor for both MMNAT and TBNAT. The MMNAT structure has been solved to 2.1 Å resolution following crystallisation in the presence of hydralazine and is compared to available NAT structures. From the mode of ligand binding, features of the binding pocket can be identified, which point to a novel mechanism for the acetylation reaction that results in a 3-methyltriazolo[3,4-a]phthalazine ring compound as product

Analysis of beta-amino alcohols as inhibitors of the potential anti-tubercular target N-acetyltransferase

The synthesis and inhibitory potencies of a novel series of β-amino alcohols, based on the hit-compound 3-[3'-(4''-cyclopent-2'''-en-1'''-ylphenoxy)-2'-hydroxypropyl]-5,5 dimethylimidazolidine-2,4-dione as specific inhibitors of mycobacterial N-acetyltransferase (NAT) enzymes are reported. Effects of synthesised compounds on growth of Mycobacterium tuberculosis have been determined