Allosteric site modulators: a case study for falcipains as malarial drug targets

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

Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: combined study of molecular modeling and dynamic residue network analysis

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

Mechanism of action of non-synonymous single nucleotide variations associated with α-carbonic anhydrase II deficiency:

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

In silico study of Plasmodium 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) for identification of novel inhibitors from SANCDB:

In this study, we intended to find potential 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) inhibitors as antimalarial drugs from the South African National Compound Database (SANCDB; https://sancdb.rubi.ru.ac.za) using computational tools

Understanding the Pyrimethamine drug resistance mechanism via combined molecular dynamics and dynamic residue network analysis:

In this era of precision medicine, insights into the resistance mechanism of drugs are integral for the development of potent therapeutics. Here, we sought to understand the contribution of four point mutations (N51I, C59R, S108N, and I164L) within the active site of the malaria parasite enzyme dihydrofolate reductase (DHFR) towards the resistance of the antimalarial drug pyrimethamine. Homology modeling was used to obtain full-length models of wild type (WT) and mutant DHFR. Molecular docking was employed to dock pyrimethamine onto the generated structures. Subsequent all-atom molecular dynamics (MD) simulations and binding free-energy computations highlighted that pyrimethamine’s stability and affinity inversely relates to the number of mutations within its binding site and, hence, resistance severity

Probing the structural dynamics of the Plasmodium falciparum tunneling-fold enzyme 6-pyruvoyl tetrahydropterin synthase to reveal allosteric drug targeting sites:

The de novo folate synthesis pathway is a well-established drug target in the treatment of many infectious diseases. Antimalarial antifolate drugs have proven to be effective against malaria, however, rapid drug resistance has emerged on the two primary targeted enzymes: dihydrofolate reductase and dihydroptoreate synthase. The need to identify alternative antifolate drugs and novel metabolic targets is of imminent importance. The 6-pyruvol tetrahydropterin synthase (PTPS) enzyme belongs to the tunneling fold protein superfamily which is characterized by a distinct central tunnel/cavity. The enzyme catalyzes the second reaction step of the parasite’s de novo folate synthesis pathway and is responsible for the conversion of 7,8-dihydroneopterin to 6-pyruvoyl-tetrahydropterin. In this study, we examine the structural dynamics of Plasmodium falciparum PTPS using the anisotropic network model, to elucidate the collective motions that drive the function of the enzyme and identify potential sites for allosteric modulation of its binding properties

Novel potential antimalarials through drug repurposing and multitargeting: a Computational Approach

This study aims to identify potential antimalarials from Food and Drug Administration (FDA) approved drugs

Impact of emerging mutations on the dynamic properties the SARS-CoV-2 main protease: an in silico investigation

The new coronavirus (SARS-CoV-2) is a global threat to world health and its economy. Its main protease (Mpro), which functions as a dimer, cleaves viral precursor proteins in the process of viral maturation. It is a good candidate for drug development owing to its conservation and the absence of a human homolog. An improved understanding of the protein behaviour can accelerate the discovery of effective therapies in order to reduce mortality. 100 ns all-atom molecular dynamics simulations of 50 homology modelled mutant Mpro dimers were performed at pH 7 from filtered sequences obtained from the GISAID database. Protease dynamics were analysed using RMSD, RMSF, Rg, the averaged betweenness centrality and geometry calculations. Domains from each Mpro protomer were found to generally have independent motions, while the dimer-stabilising N-finger region was found to be flexible in most mutants

Allosteric Modulation of Human Hsp90α Conformational Dynamics:

Central to Hsp90’s biological function is its ability to interconvert between various conformational states. Drug targeting of Hsp90’s regulatory mechanisms, including its modulation by cochaperone association, presents as an attractive therapeutic strategy for Hsp90 associated pathologies. In this study, we utilized homology modeling techniques to calculate full-length structures of human Hsp90α in closed and partially open conformations and used these structures as a basis for several molecular dynamics based analyses aimed at elucidating allosteric mechanisms and modulation sites in human Hsp90α