Cheminformatics techniques in antimalarial drug discovery and development from natural products 1: basic concepts

2019 ◽  
Vol 4 (7) ◽  
Author(s):  
Samuel Egieyeh ◽  
Sarel F. Malan ◽  
Alan Christoffels
Keyword(s):  
Natural Products ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Drug Discovery And Development ◽  
Drug Candidates ◽  
Structure Activity ◽  
Preclinical And Clinical Studies ◽  
Research Cost

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in vitro antiplasmodial activities. Facilitating antimalarial drug development from this wealth of natural products is an imperative and laudable mission to pursue. However, limited manpower, high research cost coupled with high failure rate during preclinical and clinical studies might militate against the pursuit of this mission. These limitations may be overcome with cheminformatic techniques. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of cheminformatics techniques (including molecular diversity analysis, quantitative-structure activity/property relationships and Machine learning) to natural products with in vitro and in vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

Cheminformatics techniques in antimalarial drug discovery and development from natural products 2: Molecular scaffold and machine learning approaches

2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Samuel Egieyeh ◽  
Sarel F. Malan ◽  
Alan Christoffels
Keyword(s):  
Machine Learning ◽  
Natural Products ◽  
Predictive Modeling ◽  
Antimalarial Drug ◽  
Learning Approaches ◽  
Molecular Scaffold ◽  
Drug Discovery And Development ◽  
Drug Candidates

Abstract A large number of natural products, especially those used in ethnomedicine of malaria, have shown varying in-vitro antiplasmodial activities. Cheminformatics involves the organization, integration, curation, standardization, simulation, mining and transformation of pharmacology data (compounds and bioactivity) into knowledge that can drive rational and viable drug development decisions. This chapter will review the application of two cheminformatics techniques (including molecular scaffold analysis and bioactivity predictive modeling via Machine learning) to natural products with in-vitro and in-vivo antiplasmodial activities in order to facilitate their development into antimalarial drug candidates and design of new potential antimalarial compounds.

scholarly journals Cryptosporidiosis: A Potential Anti-diarrheal Natural Product Drug Discovery Journey in Ghana, West Africa

2020 ◽  
pp. 85-93
Author(s):  
Senyo K. Botchie ◽  
Andrew G. Mtewa ◽  
Irene Ayi
Keyword(s):  
Developing Countries ◽  
Natural Products ◽  
Drug Discovery ◽  
Drug Development ◽  
Natural Product ◽  
Causative Organism ◽  
Drug Candidates ◽  
Cause Of Deaths

The overwhelming resistance to current drugs and the exhaustion of drug development interventions, as well as synthetic libraries, have compelled researchers to resort to the use of novel drug candidates derived from natural products. Cryptosporidium, the causative organism of Cryptosporidiosis, is no exception. The diarrhea-causing parasite is known to be the leading cause of deaths in children below age 5 in developing countries like Ghana and second to rotavirus as the causative agent for diarrhea in newborn calves and infants. Currently, the only FDA approved drug for the treatment of Cryptosporidiosis is Nitazoxanide. It is, therefore, needful to develop novel alternative candidates as it could aid in the decrease in child mortality and malnutrition in developing countries. Even though there have been significant limitations into anti-cryptosporidial drug development in vitro and in vivo, essential advancements are being made of which this article addresses the need for research into natural products. Some studies outlined in this paper has stated potential plant extracts showing anti-cryptosporidiosis efficacy. With the wealth of medicinal plant products and Cryptosporidium in vitro culture expertise available in our labs at Noguchi Memorial Institute for Medical research we are certain of making potential significant strides in the world of natural product Cryptosporidium drug discovery in Africa.

scholarly journals In Vitro Immune Organs-on-Chip for Drug Development: A Review

Pharmaceutics ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 278 ◽  
Author(s):  
Aya Shanti ◽  
Jeremy Teo ◽  
Cesare Stefanini
Keyword(s):  
Immune System ◽  
Drug Development ◽  
Attrition Rate ◽  
Human Immune System ◽  
Drug Candidates ◽  
Immune Organs ◽  
On Chip ◽  
High Attrition Rate

The current drug development practice lacks reliable and sensitive techniques to evaluate the immunotoxicity of drug candidates, i.e., their effect on the human immune system. This, in part, has resulted in a high attrition rate for novel drugs candidates. Organ-on-chip devices have emerged as key tools that permit the study of human physiology in controlled in vivo simulating environments. Furthermore, there has been a growing interest in developing the so called “body-on-chip” devices to better predict the systemic effects of drug candidates. This review describes existing biomimetic immune organs-on-chip, highlights their physiological relevance to drug development and discovery and emphasizes the need for developing comprehensive immune system-on-chip models. Such immune models can enhance the performance of novel drug candidates during clinical trials and contribute to reducing the high attrition rate as well as the high cost associated with drug development.

scholarly journals Replication of Plasmodium in reticulocytes can occur without hemozoin formation, resulting in chloroquine resistance

2015 ◽  
Vol 212 (6) ◽  
pp. 893-903 ◽  
Author(s):  
Jing-wen Lin ◽  
Roberta Spaccapelo ◽  
Evelin Schwarzer ◽  
Mohammed Sajid ◽  
Takeshi Annoura ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Development ◽  
Antimalarial Drug ◽  
Malaria Parasite ◽  
Chloroquine Resistance ◽  
Malaria Parasites ◽  
Human Malaria ◽  
Complete Development

Most studies on malaria-parasite digestion of hemoglobin (Hb) have been performed using P. falciparum maintained in mature erythrocytes, in vitro. In this study, we examine Plasmodium Hb degradation in vivo in mice, using the parasite P. berghei, and show that it is possible to create mutant parasites lacking enzymes involved in the initial steps of Hb proteolysis. These mutants only complete development in reticulocytes and mature into both schizonts and gametocytes. Hb degradation is severely impaired and large amounts of undigested Hb remains in the reticulocyte cytoplasm and in vesicles in the parasite. The mutants produce little or no hemozoin (Hz), the detoxification by-product of Hb degradation. Further, they are resistant to chloroquine, an antimalarial drug that interferes with Hz formation, but their sensitivity to artesunate, also thought to be dependent on Hb degradation, is retained. Survival in reticulocytes with reduced or absent Hb digestion may imply a novel mechanism of drug resistance. These findings have implications for drug development against human-malaria parasites, such as P. vivax and P. ovale, which develop inside reticulocytes.

Current development of integrated web servers for preclinical safety and pharmacokinetics assessments in drug development

2020 ◽  
Author(s):  
Yi Hsiao ◽  
Bo-Han Su ◽  
Yufeng J Tseng
Keyword(s):  
Drug Development ◽  
In Vitro Tests ◽  
Web Servers ◽  
Web Based ◽  
Structural Modifications ◽  
Drug Candidates ◽  
Alternative Choice ◽  
Preclinical Safety

Abstract In drug development, preclinical safety and pharmacokinetics assessments of candidate drugs to ensure the safety profile are a must. While in vivo and in vitro tests are traditionally used, experimental determinations have disadvantages, as they are usually time-consuming and costly. In silico predictions of these preclinical endpoints have each been developed in the past decades. However, only a few web-based tools have integrated different models to provide a simple one-step platform to help researchers thoroughly evaluate potential drug candidates. To efficiently achieve this approach, a platform for preclinical evaluation must not only predict key ADMET (absorption, distribution, metabolism, excretion and toxicity) properties but also provide some guidance on structural modifications to improve the undesired properties. In this review, we organized and compared several existing integrated web servers that can be adopted in preclinical drug development projects to evaluate the subject of interest. We also introduced our new web server, Virtual Rat, as an alternative choice to profile the properties of drug candidates. In Virtual Rat, we provide not only predictions of important ADMET properties but also possible reasons as to why the model made those structural predictions. Multiple models were implemented into Virtual Rat, including models for predicting human ether-a-go-go-related gene (hERG) inhibition, cytochrome P450 (CYP) inhibition, mutagenicity (Ames test), blood–brain barrier penetration, cytotoxicity and Caco-2 permeability. Virtual Rat is free and has been made publicly available at https://virtualrat.cmdm.tw/.

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development

2019 ◽  
Vol 25 (39) ◽  
pp. 5395-5431 ◽  
Author(s):  
Fahmida Alam ◽  
Md. Asiful Islam ◽  
Mohammad Amjad Kamal ◽  
Siew Hua Gan
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Natural Products ◽  
Drug Discovery ◽  
Drug Development ◽  
Discovery Process ◽  
Drug Discovery Process

Over the years, natural products have shown success as antidiabetics in in vitro, in vivo studies and clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs, and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

scholarly journals Combining PET Biodistribution and Equilibrium Dialysis Assays to Assess the Free Brain Concentration and BBB Transport of CNS Drugs

2012 ◽  
Vol 32 (5) ◽  
pp. 874-883 ◽  
Author(s):  
Roger N Gunn ◽  
Scott G Summerfield ◽  
Cristian A Salinas ◽  
Kevin D Read ◽  
Qi Guo ◽  
...  
Keyword(s):  
Drug Development ◽  
Human Brain ◽  
Concentration Gradient ◽  
Equilibrium Dialysis ◽  
Active Efflux ◽  
Brain Concentration ◽  
Drug Candidates ◽  
Positron Emission

The passage of drugs in and out of the brain is controlled by the blood—brain barrier (BBB), typically, using either passive diffusion across a concentration gradient or active transport via a protein carrier. In-vitro and preclinical measurements of BBB penetration do not always accurately predict the in-vivo situation in humans. Thus, the ability to assay the concentration of novel drug candidates in the human brain in vivo provides valuable information for derisking of candidate molecules early in drug development. Here, positron emission tomography (PET) measurements are combined with in-vitro equilibrium dialysis assays to enable assessment of transport and estimation of the free brain concentration in vivo. The PET and equilibrium dialysis data were obtained for 36 compounds in the pig. Predicted P-glycoprotein (P-gp) status of the compounds was consistent with the PET/equilibrium dialysis results. In particular, Loperamide, a well-known P-gp substrate, exhibited a significant concentration gradient consistent with active efflux and after inhibition of the P-gp process the gradient was removed. The ability to measure the free brain concentration and assess transport of novel compounds in the human brain with combined PET and equilibrium dialysis assays can be a useful tool in central nervous system (CNS) drug development.

Technological Advances in Preclinical Drug Evaluation: The Role of -Omics Methods

2020 ◽  
Vol 27 (8) ◽  
pp. 1337-1349 ◽  
Author(s):  
Sandra Kraljević Pavelić ◽  
Elitza Markova-Car ◽  
Marko Klobučar ◽  
Lana Sappe ◽  
Radan Spaventi
Keyword(s):  
Drug Development ◽  
Drug Evaluation ◽  
Legal Aspects ◽  
Drug Candidates ◽  
Technological Advances ◽  
Preclinical Drug Development ◽  
New Chemical Entities ◽  
Speed Up

Preclinical drug development is an essential step in the drug development process where the evaluation of new chemical entities occurs. In particular, preclinical drug development phases include deep analysis of drug candidates’ interactions with biomolecules/targets, their safety, toxicity, pharmacokinetics, metabolism by use of assays in vitro and in vivo animal assays. Legal aspects of the required procedures are well-established. Herein, we present a comprehensive summary of current state-of-the art approaches and techniques used in preclinical studies. In particular, we will review the potential of new, -omics methods and platforms for mechanistic evaluation of drug candidates and speed-up of the preclinical evaluation steps.

scholarly journals Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome

2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Aliesha L Griffin ◽  
Priyadarshini Jaishankar ◽  
Jean-Marc Grandjean ◽  
Steven H Olson ◽  
Adam R Renslo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Serotonin Receptors ◽  
Treatment Options ◽  
Dravet Syndrome ◽  
Antiepileptic Activity ◽  
Drug Candidates ◽  
Structure Activity ◽  
Life Threatening

Abstract Dravet syndrome is a life-threatening early-onset epilepsy not well controlled by antiepileptic drugs. Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. To investigate the serotonin receptors that could moderate this antiepileptic activity, we designed and synthesized 28 novel analogues of clemizole, obtained receptor binding affinity profiles, and performed in vivo screening in a scn1lab mutant zebrafish (Danio rerio) model which recapitulates critical clinical features of Dravet syndrome. We discovered three clemizole analogues with 5-HT receptor binding that exert powerful antiepileptic activity. Based on structure–activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT2B receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs.

scholarly journals Effective generation of glucosylpiericidins with selective cytotoxicities and insights into their biosynthesis

2021 ◽  
Author(s):  
Zengzhi Liu ◽  
Fei Xiao ◽  
Siqi Cai ◽  
Chunni Liu ◽  
Huayue Li ◽  
...  
Keyword(s):  
Natural Products ◽  
Cell Line ◽  
Cancer Cell Line ◽  
Wide Distribution ◽  
Solid Cancer ◽  
Bioactive Natural Products ◽  
Drug Candidates ◽  
Hct 116

Exploring unknown glycosyltransferases (GTs) is important for compound structural glycodiversification during the search for drug candidates. Piericidin glycosides have been reported to have potent bioactivities; however, the GT responsible for piericidin glucosylation remains unknown. Herein, BmmGT1, a macrolide GT with broad substrate selectivity and isolated from Bacillus methylotrophicus B-9987, was found to be able to glucosylate piericidin A1 in vitro. Next, the codon-optimized GT gene, sbmGT1, which was designed based on BmmGT1, was heterologously expressed in the piericidin producer Streptomyces youssoufiensis OUC6819. Piericidin glycosides were thus significantly accumulated, leading to the identification of four new glucopiericidins (compounds 3, 4, 6, 7). Furthermore, using BmmGT1 as the probe, GT1507 was identified in the genome of S. youssoufiensis OUC6819 and demonstrated to be associated with piericidin glucosylation; the overexpression of this gene led to the identification of another new piericidin glycoside, N-acetyl glucosamine-piericidin (compound 8). Compounds 4, 7, and 8 displayed cytotoxic selectivity toward A549, A375, HCT-116, and HT-29 solid cancer cell line over THP-1 lymphoma cell line. Moreover, database mining of GT1507 homologs revealed their wide distribution in bacteria, mainly in those belonging to the High GC Gram+ and Firmicutes -clades, thus representing the potential for identification of novel tool enzymes for compound glycodiversification. IMPORTANCE Numerous bioactive natural products are appended with sugar moieties, and are often critical for their bioactivities. Glycosyltransferases (GTs) are powerful tools for the glycodiversification of natural products. Although piericidin glycosides display potent bioactivities, the GT involved in glucosylation is unclear. In this study, five new piericidin glycosides (compounds 3, 4, 6, 7, and 8) were generated following the overexpression of GT-coding genes in a piericidin producer. Three of them (compounds 4, 7 and 8) displayed cytotoxic selectivity. Notably, GT1507 was demonstrated to be related to piericidin glucosylation in vivo. Furthermore, mining of GT1507 homologs from the GenBank database revealed their wide distribution across numerous bacteria. Our findings would greatly facilitate the exploration of GTs to glycodiversify small molecules in the search of drug candidates.

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