scholarly journals Drug Discovery Inspired by Mother Nature: Seeking Natural Biochemotypes and the Natural Assembly Rules of the Biochemome

2013 ◽  
Vol 16 (2) ◽  
pp. 331 ◽  
Author(s):  
Qiong Gu ◽  
Xin Yan ◽  
Jun Xu
Keyword(s):  
Drug Discovery ◽  
Periodic Table ◽  
Drug Targets ◽  
Biological Activities ◽  
Building Blocks ◽  
Genome Project ◽  
New Paradigm ◽  
Chemical Library ◽  
Chemical Structures ◽  
Natural Building

Purpose. The Human Genome Project is producing a new biological ‘periodic table’, which defines all genes for making macromolecules (proteins, DNA, RNA, etc) and the relations between genes and their biological functions. We now need to consider whether to initiate a biochemome project aimed at discovering biochemistry’s ‘periodic table’, which would define all molecular parts for making small molecules (natural products) and the relations between the parts and their functions to regulate genes. By understanding the Biochemome, we might be able to design biofunctional molecules based upon a set of molecular parts for drug innovation. Methods. A number of algorithms for processing chemical structures are used to systematically derive chemoyls (natural building blocks) from a database of compounds identified in Traditional Chinese Medicine (TCM). The rules to combine chemoyls for biological activities are then deduced by mining an annotated TCM structure-activity database (ATCMD). Based upon the rules and the basic chemoyls, a chemical library can be biochemically profiled, virtual synthetic routes can be planned, and lead compounds can be identified for a specific drug target. Conclusions. The Biochemome is the complete set of molecular components (chemoyls) in an organism and Biochemomics studies the rules governing their assembly and their evolution, together with the relations between the Biochemome and drug targets. This approach provides a new paradigm for drug discovery that is based on a comprehensive knowledge of the synthetic origins of biochemical diversity, and helps to direct biomimetic syntheses aimed at assembling quasi-natural product libraries for drug screening.   This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

A new paradigm for drug discovery: integrating clinical, genetic, genomic and molecular phenotype data to identify drug targets

2003 ◽  
Vol 31 (2) ◽  
pp. 437-443 ◽  
Author(s):  
E.E. Schadt ◽  
S.A. Monks ◽  
S.H. Friend
Keyword(s):  
Drug Discovery ◽  
Complex Traits ◽  
Drug Targets ◽  
Drug Discovery Process ◽  
New Paradigm ◽  
Molecular Phenotype ◽  
Clinical Genetic ◽  
Clinical Trait ◽  
Phenotype Data ◽  
The Many

Application of statistical genetics approaches to variations in mRNA transcript abundances in segregating populations can be used to identify genes and pathways associated with common human diseases. The combination of this genetic information with gene expression and clinical trait data can also be used to identify subtypes of a disease and the genetic loci specific to each subtype. Here we highlight results from some of our recent work in this area and further explore the many possibilities that exist in employing a more comprehensive genetics and functional genomics approach to the functional annotation of genomes, and in applying such methods to the validation of targets for complex traits in the drug discovery process.

scholarly journals Recent Advances in In Silico Target Fishing

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5124 ◽  
Author(s):  
Salvatore Galati ◽  
Miriana Di Stefano ◽  
Elisa Martinelli ◽  
Giulio Poli ◽  
Tiziano Tuccinardi
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Drug Targets ◽  
Biological Activities ◽  
Protein Structures ◽  
Drug Repurposing ◽  
Specific Protein ◽  
Protein Targets ◽  
Drug Candidates ◽  
Target Fishing

In silico target fishing, whose aim is to identify possible protein targets for a query molecule, is an emerging approach used in drug discovery due its wide variety of applications. This strategy allows the clarification of mechanism of action and biological activities of compounds whose target is still unknown. Moreover, target fishing can be employed for the identification of off targets of drug candidates, thus recognizing and preventing their possible adverse effects. For these reasons, target fishing has increasingly become a key approach for polypharmacology, drug repurposing, and the identification of new drug targets. While experimental target fishing can be lengthy and difficult to implement, due to the plethora of interactions that may occur for a single small-molecule with different protein targets, an in silico approach can be quicker, less expensive, more efficient for specific protein structures, and thus easier to employ. Moreover, the possibility to use it in combination with docking and virtual screening studies, as well as the increasing number of web-based tools that have been recently developed, make target fishing a more appealing method for drug discovery. It is especially worth underlining the increasing implementation of machine learning in this field, both as a main target fishing approach and as a further development of already applied strategies. This review reports on the main in silico target fishing strategies, belonging to both ligand-based and receptor-based approaches, developed and applied in the last years, with a particular attention to the different web tools freely accessible by the scientific community for performing target fishing studies.

scholarly journals Structures and Biological Activities of Diketopiperazines from Marine Organisms: A Review

Marine Drugs ◽  
2021 ◽  
Vol 19 (8) ◽  
pp. 403
Author(s):  
Zhiqiang Song ◽  
Yage Hou ◽  
Qingrong Yang ◽  
Xinpeng Li ◽  
Shaohua Wu
Keyword(s):  
Drug Discovery ◽  
Natural Product ◽  
Biological Activities ◽  
Review Article ◽  
Membered Ring ◽  
Marine Organisms ◽  
Biological Functions ◽  
Chemical Structures ◽  
Marine Habitats ◽  
Long Time

Diketopiperazines are potential structures with extensive biological functions, which have attracted much attention of natural product researchers for a long time. These compounds possess a stable six-membered ring, which is an important pharmacophore. The marine organisms have especially been proven to be a wide source for discovering diketopiperazine derivatives. In recent years, more and more interesting bioactive diketopiperazines had been found from various marine habitats. This review article is focused on the new 2,5-diketopiperazines derived from marine organisms (sponges and microorganisms) reported from the secondary half-year of 2014 to the first half of the year of 2021. We will comment their chemical structures, biological activities and sources. The objective is to assess the merit of these compounds for further study in the field of drug discovery.

scholarly journals Insights on recent approaches in drug discovery strategies and untapped drug targets against drug resistance

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ramalingam Peraman ◽  
Sathish Kumar Sure ◽  
V. N. Azger Dusthackeer ◽  
Naresh Babu Chilamakuru ◽  
Padmanabha Reddy Yiragamreddy ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Drug Targets ◽  
Genetic Research ◽  
Integrated Approach ◽  
Main Body ◽  
Chemical Structures ◽  
New Drug ◽  
Discovery Research ◽  
Drug Discovery Research

Abstract Background Despite the various strategies undertaken in the clinical practice, the mortality rate due to antibiotic-resistant microbes has been markedly increasing worldwide. In addition to multidrug-resistant (MDR) microbes, the “ESKAPE” bacteria are also emerging. Of course, the infection caused by ESKAPE cannot be treated even with lethal doses of antibiotics. Now, the drug resistance is also more prevalent in antiviral, anticancer, antimalarial and antifungal chemotherapies. Main body To date, in the literature, the quantum of research reported on the discovery strategies for new antibiotics is remarkable but the milestone is still far away. Considering the need of the updated strategies and drug discovery approaches in the area of drug resistance among researchers, in this communication, we consolidated the insights pertaining to new drug development against drug-resistant microbes. It includes drug discovery void, gene paradox, transposon mutagenesis, vitamin biosynthesis inhibition, use of non-conventional media, host model, target through quorum sensing, genomic-chemical network, synthetic viability to targets, chemical versus biological space, combinational approach, photosensitization, antimicrobial peptides and transcriptome profiling. Furthermore, we optimally briefed about antievolution drugs, nanotheranostics and antimicrobial adjuvants and then followed by twelve selected new feasible drug targets for new drug design against drug resistance. Finally, we have also tabulated the chemical structures of potent molecules against antimicrobial resistance. Conclusion It is highly recommended to execute the anti-drug resistance research as integrated approach where both molecular and genetic research needs to be as integrative objective of drug discovery. This is time to accelerate new drug discovery research with advanced genetic approaches instead of conventional blind screening.

scholarly journals Trichoderma: A Treasure House of Structurally Diverse Secondary Metabolites With Medicinal Importance

2021 ◽  
Vol 12 ◽  
Author(s):  
Jian-Long Zhang ◽  
Wen-Li Tang ◽  
Qing-Rong Huang ◽  
You-Zhi Li ◽  
Mao-Lian Wei ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Secondary Metabolites ◽  
Biological Activities ◽  
Foreseeable Future ◽  
Human History ◽  
Comprehensive Overview ◽  
Specialized Metabolites ◽  
Chemical Structures ◽  
Drug Leads ◽  
New Strategies

Fungi play an irreplaceable role in drug discovery in the course of human history, as they possess unique abilities to synthesize diverse specialized metabolites with significant medicinal potential. Trichoderma are well-studied filamentous fungi generally observed in nature, which are widely marketed as biocontrol agents. The secondary metabolites produced by Trichoderma have gained extensive attention since they possess attractive chemical structures with remarkable biological activities. A large number of metabolites have been isolated from Trichoderma species in recent years. A previous review by Reino et al. summarized 186 compounds isolated from Trichoderma as well as their biological activities up to 2008. To update the relevant list of reviews of secondary metabolites produced from Trichoderma sp., we provide a comprehensive overview in regard to the newly described metabolites of Trichoderma from the beginning of 2009 to the end of 2020, with emphasis on their chemistry and various bioactivities. A total of 203 compounds with considerable bioactivities are included in this review, which is worth expecting for the discovery of new drug leads and agrochemicals in the foreseeable future. Moreover, new strategies for discovering secondary metabolites of Trichoderma in recent years are also discussed herein.

scholarly journals Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery

2021 ◽  
Vol 14 (12) ◽  
pp. 1275
Author(s):  
Tony Ge ◽  
Jean-Christophe Cintrat
Keyword(s):  
Drug Discovery ◽  
Bioactive Compounds ◽  
Biological Activities ◽  
Building Blocks ◽  
Biological Properties ◽  
Extensive Review ◽  
Complex Molecules ◽  
New Chemical Entities ◽  
Amino Derivatives

Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the (fused) rings). In a constant quest for new chemical entities in drug discovery, a few novel heterocycles have emerged in recent years as promising building blocks for the obtainment of bioactive modulators. In this context, pyrrolotriazinones have attracted attention, and some show promising biological activities. Here, we offer an extensive review of pyrrolo[2,1-f][1,2,4]triazin-4(1H)-one and pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, describing their biological properties en route to drug discovery.

Screening of Natural Lead Molecules Against Putative Molecular Targets of Drug-resistant Cryptococcus spp: An Insight from Computer-aided Molecular Design

2019 ◽  
Vol 18 (31) ◽  
pp. 2681-2701
Author(s):  
Meghna Manjunath ◽  
Sinosh Skariyachan
Keyword(s):  
Drug Discovery ◽  
Virtual Screening ◽  
Drug Targets ◽  
Medicinal Chemistry ◽  
Fungal Infections ◽  
Limited Information ◽  
New Paradigm ◽  
Effective Prevention ◽  
Computer Aided

Cryptococcosis is one of the major invasive fungal infections distributed worldwide with high mortality rate. C. neoformans and C. gattii are the major organisms that cause various types of infections. Anti-fungal resistances exhibited by the mentioned species of Cryptococcus threaten their effective prevention and treatment. There is limited information available on human to human transmission of the pathogen and virulent factors that are responsible for Cryptococcus mediated infections. Hence, there is high scope for understanding the mechanism, probable drug targets and scope of developing natural therapeutic agents that possess high relevance to pharmaceutical biotechnology and medicinal chemistry. The proposed review illustrates the role of computer-aided virtual screening for the screening of probable drug targets and identification of natural lead candidates as therapeutic remedies. The review initially focuses on the current perspectives on cryptococcosis, major metabolic pathways responsible for the pathogenesis, conventional therapies and associated drug resistance, challenges and scope of structure-based drug discovery. The review further illustrates various approaches for the prediction of unknown drug targets, molecular modeling works, screening of natural compounds by computational virtual screening with ideal drug likeliness and pharmacokinetic features, application of molecular docking studies and simulation. Thus, the present review probably provides AN insight into the role of medicinal chemistry and computational drug discovery to combat Cryptococcus infections and thereby open a new paradigm for the development of novel natural therapeutic against various drug targets for cryptococcal infections.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids

2018 ◽  
Vol 18 (5) ◽  
pp. 321-368 ◽  
Author(s):  
Juan A. Bisceglia ◽  
Maria C. Mollo ◽  
Nadia Gruber ◽  
Liliana R. Orelli
Keyword(s):  
Drug Targets ◽  
Redox Homeostasis ◽  
Cost Effective ◽  
Structural Features ◽  
Mammalian Host ◽  
Neglected Diseases ◽  
Nitrogen Compounds ◽  
Chemical Structures

Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed.

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