Allosteric site modulators: a case study for falcipains as malarial drug targets
- Authors: Musyoka, Thommas M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162699 , vital:40974 , https://doi.org/10.21955/gatesopenres.1116459.1
- Description: Fighting against malaria is a never-ending battle. Plasmodium parasites continuously develop resistance to the drugs used against them including the artemisinin-based combination therapies as observed recently in Southeast Asia. The main concern now is whether the resistant parasite strains spread to Africa, where most malaria cases are located. To prevent this, we need to think outside the box. To date, there is no allosteric drug for malaria. Hence, allosteric drug targeting sites and modulators might be a new hope for malarial treatment. In Plasmodium falciparum two cysteine proteases, falcipain-2 (FP-2) and falcipain-3 (FP-3), have been identified as the main hemoglobinases, and are considered as attractive drug targets.
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- Date Issued: 2019
Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: combined study of molecular modeling and dynamic residue network analysis
- Authors: Amusengeri, Arnold , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162949 , vital:40999 , https://doi.org/10.3390/molecules24010188
- Description: The human heat shock proteins (Hsps), predominantly Hsp72 and Hsp90, have been strongly implicated in various critical stages of oncogenesis and progression of human cancers. While drug development has extensively focused on Hsp90 as a potential anticancer target, much less effort has been put against Hsp72. This work investigated the therapeutic potential of Hsp72 and its constitutive isoform, Hsc70, via in silico-based screening against the South African Natural Compounds Database (SANCDB). A comparative modeling approach was used to obtain nearly full-length 3D structures of the closed conformation of Hsp72 and Hsc70 proteins. Molecular docking of SANCDB compounds identified one potential allosteric modulator, Discorhabdin N, binding to the allosteric β substrate binding domain (SBDβ) back pocket, with good binding affinities in both cases.
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- Date Issued: 2019
Establishing computational approaches towards identifying malarial allosteric modulators: a case study of plasmodium falciparum hsp70s
- Authors: Amusengeri, Arnold , Astl, Lindy , Lobb, Kevin A , Verkhivker, Gennady M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/163000 , vital:41003 , https://doi.org/10.3390/ijms20225574
- Description: Combating malaria is almost a never-ending battle, as Plasmodium parasites develop resistance to the drugs used against them, as observed recently in artemisinin-based combination therapies. The main concern now is if the resistant parasite strains spread from Southeast Asia to Africa, the continent hosting most malaria cases. To prevent catastrophic results, we need to find non-conventional approaches. Allosteric drug targeting sites and modulators might be a new hope for malarial treatments. Heat shock proteins (HSPs) are potential malarial drug targets and have complex allosteric control mechanisms. Yet, studies on designing allosteric modulators against them are limited. Here, we identified allosteric modulators (SANC190 and SANC651) against P. falciparum Hsp70-1 and Hsp70-x, affecting the conformational dynamics of the proteins, delicately balanced by the endogenous ligands. Previously, we established a pipeline to identify allosteric sites and modulators. This study also further investigated alternative approaches to speed up the process by comparing all atom molecular dynamics simulations and dynamic residue network analysis with the coarse-grained (CG) versions of the calculations. Betweenness centrality (BC) profiles for PfHsp70-1 and PfHsp70-x derived from CG simulations not only revealed similar trends but also pointed to the same functional regions and specific residues corresponding to BC profile peaks.
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- Date Issued: 2019
Mechanism of action of non-synonymous single nucleotide variations associated with α-carbonic anhydrase II deficiency:
- Authors: Sanyanga, Taremekedzwa A , Nizami, Bilal , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162655 , vital:40970 , https://doi.org/10.3390/molecules24213987
- Description: Human carbonic anhydrase II (CA-II) is a Zinc (Zn 2+ ) metalloenzyme responsible for maintenance of acid-base balance within the body through the reversible hydration of CO 2 to produce protons (H + ) and bicarbonate (BCT). Due to its importance, alterations to the amino acid sequence of the protein as a result of single nucleotide variations (nsSNVs) have detrimental effects on homeostasis. Six pathogenic CA-II nsSNVs, K18E, K18Q, H107Y, P236H, P236R and N252D were identified, and variant protein models calculated using homology modeling. The effect of each nsSNV was analyzed using motif analysis, molecular dynamics (MD) simulations, principal component (PCA) and dynamic residue network (DRN) analysis. Motif analysis identified 11 functionally important motifs in CA-II.
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- Date Issued: 2019
South African Abietane Diterpenoids and their analogs as potential antimalarials: novel insights from hybrid computational approaches
- Authors: Musyoka, Thommas M , Tastan Bishop, Özlem
- Date: 2019
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/162665 , vital:40971 , https://doi.org/10.3390/molecules24224036
- Description: The hemoglobin degradation process in Plasmodium parasites is vital for nutrient acquisition required for their growth and proliferation. In P. falciparum, falcipains (FP-2 and FP-3) are the major hemoglobinases, and remain attractive antimalarial drug targets. Other Plasmodium species also possess highly homologous proteins to FP-2 and FP-3. Although several inhibitors have been designed against these proteins, none has been commercialized due to associated toxicity on human cathepsins (Cat-K, Cat-L and Cat-S). Despite the two enzyme groups sharing a common structural fold and catalytic mechanism, distinct active site variations have been identified, and can be exploited for drug development. Here, we utilize in silico approaches to screen 628 compounds from the South African natural sources to identify potential hits that can selectively inhibit the plasmodial proteases.
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- Date Issued: 2019