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Fundamental physical and chemical concepts behind “drug-likeness” and “natural product-likeness”

  • Mohd Athar ORCID logo EMAIL logo , Alfred Ndeme Sona , Boris Davy Bekono and Fidele Ntie-Kang
From the journal Physical Sciences Reviews

Abstract

The discovery of a drug is known to be quite cumbersome, both in terms of the microscopic fundamental research behind it and the industrial scale manufacturing process. A major concern in drug discovery is the acceleration of the process and cost reduction. The fact that clinical trials cannot be accelerated, therefore, emphasizes the need to accelerate the strategies for identifying lead compounds at an early stage. We, herein, focus on the definition of what would be regarded as a “drug-like” molecule and a “lead-like” one. In particular, “drug-likeness” is referred to as resemblance to existing drugs, whereas “lead-likeness” is characterized by the similarity with structural and physicochemical properties of a “lead”compound, i.e. a reference compound or a starting point for further drug development. It is now well known that a huge proportion of the drug discovery is inspired or derived from natural products (NPs), which have larger complexity as well as size when compared with synthetic compounds. Therefore, similar definitions of “drug-likeness” and “lead-likeness” cannot be applied for the NP-likeness. Rather, there is the dire need to define and explain NP-likeness in regard to chemical structure. An attempt has been made here to give an overview of the general concepts associated with NP discovery, and to provide the foundational basis for defining a molecule as a “drug”, a “lead” or a “natural compound.”

Acknowledgements

MA acknowledges the generous support from the Department of Science and Technology (DST), Government of India in the form of SRF-INSPIRE fellowship (IF150167) and Central University of Gujarat, India. FNK acknowledges a return fellowship and an equipment subsidy from the Alexander von Humboldt Foundation, Germany. BDB thanks the African-German Network of Excellence in Science (AGNES) for granting a Mobility Grant in 2017, generously sponsored by German Federal Ministry of Education and Research and the Alexander von Humboldt Foundation, Germany. Financial support for this work is acknowledged from a ChemJets fellowship from the Ministry of Education, Youth and Sports of the Czech Republic awarded to FNK.

List of abbreviations

Abbreviation

Full meaning

ADME

absorption, distribution, metabolism, and excretion

ADME/tox

absorption, distribution, metabolism, excretion and toxicity

bRo5

beyond the Ro5

clogP

the calculated logarithm of the n-octanol/water partition coefficient

CASE

computer assisted structure elucidation

DNP

Dictionary of Natural Products

FBDD

Fragment-based drug design

Fsp3

sp3-hybridized carbon atoms

HBA

number of hydrogen-bond acceptors

HBD

number of hydrogen-bond donors

MR

molar refractivity

MW

molecular weight

NCEs

new chemical entities

NP

natural product

NRB

number of rotatable bonds

PBF

the plane of Best Fit

PCA

principal component analysis

PMI

Principal Moment of Inertia

PPI

protein–protein interactions

PSA

polar surface area

QED

quantitative estimate of drug-likeness

QSAR

quantitative structure–activity relationships

Ro3

“Rule of three”

Ro5

“Rule of five”

SCONP

Structural Classification of Natural Products

TPSA

total polar surface area

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Published Online: 2019-09-04

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