Strategic application of in silico drug discovery approaches to discover novel TB drugs = Ukusetshenziswa komqondosu womuthi wokwelapha i-in silico ngezindlelakwenza ukuze kutholakale imithi yokwelapha i-TB emisha.

Abstract

Tuberculosis is one of the major causes of mortality worldwide due to the onset of bacterial infection. It remains a continuous field of study as a result of the emergence of drug resistant strains whereby first- and second-line drugs are ineffective. Variations associated with proteins in the bacteria, Mycobacterium tuberculosis, can be attributed largely to poor compliance of patients and the existence of co-morbidities within a person, inevitably leading to coinfections and a diminished immune response. This evolution of the bacteria therefore calls for extensive research to be carried out on enhanced drug design and development techniques. Re-evaluation of previously identified drug targets, determination of newly viable drug targets and the identification and design of small molecule inhibitors form a basis on the forefront of this research. Computer aided drug design techniques provide a novel method exponentially gaining popularity. Molecular modelling utilizing in silico developed methods, paired with drug repurposing, pose a viable, cost effective and efficient solution for drug design strategies. The use of chemical interaction data associated with small molecules forming complexes with drug targets of interest help understand the behaviour and mechanism of a protein before graduating to wet method techniques. Using the fundamentals of docking, molecular dynamics and virtual screening, various small molecules with the potential to provide extensive inhibition capability can be identified. This study investigates three major drug targets of Mycobacterium tuberculosis (Mtb): Enoyl-[acyl-carrier-protein] reductase (inhA), β-ketoacyl ACP synthase (KasA), and Dihydropteroate synthase (DHPS/folP1) involved in the mycolic acid and folate pathways. Various tools inclusive of gene ontology, network-based inference, virtual screening and tailored pharmacophore as a function of molecular modelling and drug repurposing were used to identify potential potent inhibitors and comprehend the understanding of the structural changes, conformations and interactions associated with the protein and the response to suggested drug hits with the potential to affect an overall protein structure in consideration with the formation of a complex. This approach can potentially serve as a platform to the development and discovery of novel drugs against a wide range of drug targets.

Iqoqa.

Isifo sofuba singezinye zezimbangela ezinkulu zokushona emhlabeni jikelele ngenxa yokuthathelwana kwezifo zamagciwane. Silokhu siqhubeka nokuba wumkhakha ocwaningwayo ngenxa yokuqubuka kwezinhlobo ezingezweli emithini yokwelapha lapho imithi esetshenziswe ezingeni lokuqala nelesibili ingasebenzi. Umehluko ohlobene nezakhamzimba amaphrotheyni asegciwaneni iMycobacterium tuberculosis, kungahlotshaniswa kakhulu nokuhambisana okungekuhle kweziguli nobukhona bezinye izifo kumuntu, okuholela ekuthelelekeni ngokuningi nokwenza izinga lamasosha omzimba ehle. Le nguqukomumo yegciwane ibiza ukuba kube nocwaningo olunzulu okumele lwenziwe ngohlelo lwemithi ephuculiwe namasu okuluphucula. Ukuhlola kabusha kwemithi ebihlonzwe esikhathini esedlule ukuhlonzwa kokuhloswe ngemithi yokwelapha nesakhiwo sezivimbi zamamolekhyuli amancane kuyisisekelo esiphambili kulolu cwaningo. Amasukhono emithi ehlanganiswe ngokwekhompyutha ahlinzeka indlela esazanywa enokuthandwa okukhula kakhulu. Ukuqondisa amamolekhyuli asetshenziswa ezindleleni ezakhelwe i-in silico, ahambelaniswa nokusetshenziselwa ezinye izifo kwemithi, okuqhamuka isixazululo esinezindleko eziphansi nezisebenza ngezindlela zamasu okwakha imithi. Ukusetshenziswa kwemininingo yokuxutshwa kwamakhemikhali okuhlobene namamolekhyuli amancane kwakha izinhlanganisela zemithi okusoshwe ukusiza ukuqonda insebenzo kanye nendlela yephrotheyni ngaphambi kokuba kwedlulelwe emaswini ayizindlela zokumanzisa. Kusetshenziswa izingqikithi zokuzimelelisa, amadayinamikhi amamolekhyuli nokuskrina ungekho endaweni, amamolekhyuli amancane ayizinhlobo ezehlukene ezingakwazi ukuhlinzeka ukukwazi ukuvimbela okusezingeni elikhulu okungahlonzwa. Lolu cwaningo luphenya izinhlobo ezintathu zemithi esoshelwe ukusetshenziselwa i-Mycobacterium tuberculosis (Mtb): i-Enoyl-[acyl-carrier-protein] reductase (inhA), i-β-ketoacyl ACP synthase (KasA), neDihydropteroate synthase (DHPS/folP1) efakwe emigudwini yemycolic acid nefolate. Amathuluzi ehlukene ezinsizakusebenza ezisuselwa ekucwaningeni ngobunjalobukhona bofuzo, ukuqagulwa okususelwa ebuxhakaxhakeni, ukuskrina ungekho lapho kusetshenzelwa khona nensebenzomithi ehleliwe njengokomgomo wokwakhiwa kwamamolekhyuli nokusetshenziswa ngendlela entsha kwemithi kwenziwelwa ukuhlonza izivimbinsebenzobuthi ezikhona nokuzwa ukuqonda ushintsho lokomumo, okuhambelana nokuxhumana okuhambelana namaphrotheyni nempendulo yemithi ephakanyisiwe engaba nomthelela emumweni ophelele wephrotheyni uma kubhekwa isakhiwo senkimbingxube. Leli su lingakwazi ukuba yinkundla yentuthuko nokuthola imithi esazanywa esetshenziselwa izinhloso ezehlukene zokwelapha.