In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the ...discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field. Recently, however, there has been an upsurge of activities relying on the structural information, aimed at improving and developing other forms of metal-based compounds and nonclassical platinum complexes whose mechanism of action is distinct from known drugs such as cisplatin. In line with this, many more metal-based compounds have been synthesized by redesigning the existing chemical structure through ligand substitution or building the entire new compound with enhanced safety and cytotoxic profile. However, because of increased emphasis on the clinical relevance of metal-based complexes, a few of these drugs are currently on clinical trial and many more are awaiting ethical approval to join the trial. In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed.
This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This ...non‐randomized controlled trial included 62 patients on the triple combination treatment versus 51 age‐ and sex‐matched patients on routine supportive treatment. all of them confirmed cases by positive reverse‐transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS‐COV2 from the nasopharynx in a shorter time than symptomatic therapy.
he present art of drug discovery and design of new drugs is based on suicidal irreversible inhibitors. Covalent inhibition is the strategy that is used to achieve irreversible inhibition. ...Irreversible inhibitors interact with their targets in a time-dependent fashion, and the reaction proceeds to completion rather than to equilibrium. Covalent inhibitors possessed some significant advantages over non-covalent inhibitors such as covalent warheads can target rare, non-conserved residue of a particular target protein and thus led to development of highly selective inhibitors, covalent inhibitors can be effective in targeting proteins with shallow binding cleavage which will led to development of novel inhibitors with increased potency than non-covalent inhibitors. Several computational approaches have been developed to simulate covalent interactions; however, this is still a challenging area to explore. Covalent molecular docking has been recently implemented in the computer-aided drug design workflows to describe covalent interactions between inhibitors and biological targets. In this review we highlight: (i) covalent interactions in biomolecular systems; (ii) the mathematical framework of covalent molecular docking; (iii) implementation of covalent docking protocol in drug design workflows; (iv) applications covalent docking: case studies and (v) shortcomings and future perspectives of covalent docking. To the best of our knowledge; this review is the first account that highlights different aspects of covalent docking with its merits and pitfalls. We believe that the method and applications highlighted in this study will help future efforts towards the design of irreversible inhibitors.
The discovery and developmental processes of CNS drugs have been limited by the inability of potential drug molecules to pass through the blood-brain barrier (BBB). This presents a significant ...setback in the treatment of neurodegenerative disorders such as Alzheimer's disease (AD), hence the need for compounds that can adhere strictly to the selective criteria of suitable CNS drugs. Collapsin response mediator protein-2 (CRMP-2) has been recently identified as a viable target in neurotherapeutics due to its involvement in the etiology of AD. As shown in previous studies, Naringenin (NAR), a small molecule derivative of Drynaria rhizome (DR) extract, specifically binds CRMP-2 and reduces its phosphorylation. This was shown to facilitate axonal regrowth, with improvement in cognition and learning. Herein, we report the first account of the use of cheminformatics techniques to define the CNS drug-suitability of NAR using selective criteria, coupled with the prediction of possible biological activities and toxicities. Also, we evaluated the mechanistic activity of NAR by modeling its molecular interaction with human CRMP-2 (hCRMP-2). Physicochemical analyses revealed the suitability of NAR as a CNS drug and its ability to transverse the BBB. Possible neurogenic, anti-carcinogenic and cardioprotective activities were also predicted. NAR exhibited favorable binding to CRMP-2 and formed strong bonds with active site residues, which accounts for its stabilization and affinity. Moreover, NAR induced notable conformational changes in CRMP-2, an occurrence that could possibly disrupt kinase-mediated phosphorylation. These findings will aid in the optimization of NAR and improve its neurotherapeutic activities in the treatment of AD.
•The transport of neurotherapeutic drugs is controlled by the blood-brain barrier.•Naringenin and its derivatives can cross the blood-brain barrier.•Naringenin specifically targets Collapsin Response Mediator Protein-2.•Binding of naringenin alters Collapsin Response Mediator Protein-2 structure.•Changes in Collapsin Response Mediator Protein-2 structure reduce phosphorylation.
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•Tuberculosis is a highly infectious disease and is caused by the pathogen Mycobacterium tuberculosis.•The recent advancements in the discovery of anti-tuberculosis drugs have been ...described.•This review focusses on anti-tubercular agents that are currently in clinical trials.
Modern chemotherapy has significantly improved patient outcomes against drug-sensitive tuberculosis. However, the rapid emergence of drug-resistant tuberculosis, together with the bacterium’s ability to persist and remain latent present a major public health challenge. To overcome this problem, research into novel anti-tuberculosis targets and drug candidates is thus of paramount importance. This review article provides an overview of tuberculosis highlighting the recent advances and tools that are employed in the field of anti-tuberculosis drug discovery. The predominant focus is on anti-tuberculosis agents that are currently in the pipeline, i.e. clinical trials.
The pace and efficiency of drug target strategies have been emanating debates among researchers in the field of drug development. Covalent inhibitors possess significant advantages over non-covalent ...inhibitors, such that covalent warheads can target rare residues of a particular target protein, thus leading to the development of highly selective inhibitors. However, toxicity can be a real challenge related to this class of therapeutics. From the challenges of irreversible drug toxicity to the declining reactivity of reversible drugs, herein we provide justifications from the computational point of view. It was evident that both classes had its merits; however, with the increase in drug resistance, covalent inhibition seemed more suitable. There also seems to be enhanced selectivity of the covalent systems, proving its use as a therapeutic regimen worldwide. We believe that this study will assist researchers in making informed decisions on which drug class to choose as lead compounds in the drug discovery pipeline.
An integrated approach to designing structure-based enzymatic drugs is detailed, focusing on molecular modeling, experimental bioactivity and biophysical analytical aspects.
The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito ...vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This in silico 'per-residue energy decomposition pharmacophore' virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.
Various evidence has revealed that mutations in p53 exert activities that go beyond simply inactivation of wildtype functions but rather elicits downstream interactions that promote malignancy ...described as mutant p53 gain‐of‐function (GOF). Here we report the first account of the dynamics of mutation‐induced structural transition of native p53 to an aberrant gain‐of‐function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation. Result analysis revealed that both mutants exhibited structural distortion and reduced flexibility, indicative of rigidity and kinetic stability. In addition, surface analysis revealed an increase in the accessible surface area in the p53 mutants. This suggests that the GOF transition involves protein unfolding and exposure of buried hydrophobic surface essential for interaction with HSF‐1 oncogenic partner and wildtype p63, and p73 homologs. Further validation revealed binding cavities, similar in the mutants but dissimilar to the WT. Taken together, this study complements experimental findings and reveals the interplay between mutation‐induced structural distortion, loss of flexibility, rigidity, enhanced stability, protein unfolding and ultimately, exposure of binding surfaces as conformational attributes that characterize mutP53 structure‐GOF activities. This insight is, therefore, of great importance as it opens up a novel therapeutic approach toward the structure based targeting of mutP53 oncogenic involvement beyond wildtype inactivation. Furthermore, “exposed” binding site information obtained from this study can be explored for structure‐based design of substances best described as “destabilizers” to disrupt the GOF interaction of mutp53.
p53 mutations go beyond inactivation to oncogenic protein‐protein interaction described as gain‐of‐function (GOF). Structural distortion, loss of flexibility, unfolding, and exposure of buried core surfaces characterize GOF activities. Disrupting these interaction by structure based targeting with appropriate inhibitors would discontinue oncogenic activities of p53 mutants.
The pharmacological propensities of curcumin have been reported in a plethora of pre-clinical and clinical studies. However, innate attributes account for extremely low oral bioavailability which ...impedes its development as a therapeutic agent. Regardless, these drawbacks have not deterred researchers from optimizing its potentials. This review discussed the pharmacokinetic properties of curcumin relative to its outlook as a lead compound in drug discovery. Also, we highlighted therapeutic strategies that have expedited improvements in curcumin oral bioavailability and delivery to target sites over the years. Recent implementations of these strategies were also covered. More research efforts should be directed towards investigating the pharmacokinetic impacts of these novel curcumin formulations in human clinical studies since inter-species disparities could limit the accuracies of animal studies. We envisaged that integrative-clinical research would help determine ‘actual’ improvements in curcumin pharmacokinetics coupled with suitable administrative routes, optimal dosing, and drug–enzyme or drug–drug interactions. In addition, this could help determine formulations for achieving higher systemic exposure of parent curcumin thereby providing a strong impetus towards the development of curcumin as a drug candidate in disease treatment.
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