Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery (original) (raw)
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Developing a Drug-like Natural Product Library
Journal of Natural Products, 2008
Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs.
Journal of Computer Aided Molecular Design, 1997
This paper describes a novel methodology, PRO_SELECT, which combines elements of structure-based drug design and combinatorial chemistry to create a new paradigm for accelerated lead discovery. Starting with a synthetically accessible template positioned in the active site of the target of interest, PRO_SELECT employs database searching to generate lists of potential substituents for each substituent position on the template. These substituents are selected on the basis of their being able to couple to the template using known synthetic routes and their possession of the correct functionality to interact with specified residues in the active site. The lists of potential substituents are then screened computationally against the active site using rapid algorithms. An empirical scoring function, correlated to binding free energy, is used to rank the substituents at each position. The highest scoring substituents at each position can then be examined using a variety of techniques and a final selection is made. Combinatorial enumeration of the final lists generates a library of synthetically accessible molecules, which may then be prioritised for synthesis and assay. The results obtained using PRO_SELECT to design thrombin inhibitors are briefly discussed.
Natural Lead Compound in Drug Design
2021
Traditionally, it is highly time consuming and expensive process to design ,development and launching of new drug. Natural process research is increasingly Being combined with computer aided drug design technique by the application of chemo informatics method ,we analyze (quantify ) chemical diversity and structural complexity and distribution in chemical space. During this period of new drug development involves around 10-15 yrs and invest high cost,This is done by various researchers and scientist from various field and discipline .The discovery of new drug from natural product are new strategic option in the field of new drug discovery and used as a lead for the further process. During the last decades a large number of biological active compound was screened out from the natural product as a new drug lead compound .The natural product as a new drug lead compound .the natural sources include Plant ,Animal ,Marine-organism ,mineral and micro –organism etc..
A very large diversity space of synthetically accessible compounds for use with drug design programs
We have constructed a very large virtual diversity space containing more than 10 13 chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.
International Journal of Pharmacognosy & Chinese Medicine
Natural products have been an inherent part of sustaining acculturation because of their medicinal properties. Past discoveries of bioactive natural products have relied on serendipity and accidental experience, and these compounds serve as inspiration for the generation of analogs with desired physicochemical properties. Bioactive natural products with therapeutic potential are abundantly available in nature and some of them are beyond exploration by conventional methods. However there has been a great breakthrough in the study of computer aided drug design (CADD) as many unfruitful lab researches have been averted and money, time and energies saved through CADD. Computer-aided drug design is a stimulating, arousing and manifold discipline where various aspects of applied and basic research integrate and induce each other. The empirical basis of CADD involves quantum mechanics and molecular modeling studies like structure based drug design; ligand-based drug design; database search...
Realisation of small molecule libraries based on frameworks distantly related to natural products
Organic & biomolecular chemistry, 2018
The availability of high-quality screening compounds is of paramount importance for the discovery of innovative new medicines. Natural product (NP) frameworks can inspire the design of productive compound libraries. Here, we describe the design and synthesis of four compound libraries based on scaffolds that have broad NP-like features, but that are only distantly related to specific NPs. The optimisation of syntheses of the scaffolds using [5 + 2] cycloaddition chemistry is detailed, together with methods to yield exemplar decorated screening compounds. In each case, a library was nominated for production, leading to a total of >2900 screening compounds that augmented the Joint European Compound Library of the European Lead Factory.
Fragment-based drug design of nature-inspired compounds
Physical Sciences Reviews, 2019
Natural product (NP)-derived drugs can be extracts, biological macromolecules, or purified small molecule substances. Small molecule drugs can be originally purified from NPs, can represent semisynthetic molecules, natural fragments containing small molecules, or are fully synthetic molecules that mimic natural compounds. New semisynthetic NP-like drugs are entering the pharmaceutical market almost every year and reveal growing interests in the application of fragment-based approaches for NPs. Thus, several NP databases were constructed to be implemented in the fragment-based drug design (FBDD) workflows. FBDD has been established previously as an approach for hit identification and lead generation. Several biophysical and computational methods are used for fragment screening to identify potential hits. Once the fragments within the binding pocket of the protein are identified, they can be grown, linked, or merged to design more active compounds. This work discusses applications of ...
Natural Product Libraries to Accelerate the High-Throughput Discovery of Therapeutic Leads
Journal of Natural Products, 2011
A high throughput (HT) paradigm generating LC-MS-UV-ELSD based natural product libraries to discover compounds with new bioactivities and or molecular structures is presented. To validate this methodology an extract of the Indo Pacific marine sponge Cacospongia mycofijiensis was evaluated using assays involving cytoskeletal profiling, tumor cell lines, and parasites. Twelve known compounds were identified including the latrunculins (1-4, 10), fijianolides (5, 8-9), mycothiazole (11), the aignopsanes (6-7) and sacrotride A (13). Compounds 1-4, 5, 8-11 exhibited bioactivity not previously reported against the parasite T. brucei, while 11 showed selectivity for lymphoma (U937) tumor cell lines. Four new compounds were also discovered including: aignopsanoic acid B (13), apo latrunculin T (14), 20-methoxy-fijianolide A (15) and aignopsane ketal (16). Compounds 13 and 16 represent important derivatives of the aignopsane d Library fractions were assayed assuming ~ 0.1 mg/well. This was based on averaging the amount of extract injected to create each library [15 mg/100 µL] divided by 70 fractions ≈ 0.2 mg/well and then factoring in a loss of 50% from the generation of a reference library.
DOGS: Reaction-Driven de novo Design of Bioactive Compounds
PLoS Computational Biology, 2012
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated 'in silico' assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H 4 receptor and c-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with druglike properties.