Ligand intramolecular motions in ligand-protein interaction: ALPHA, a novel dynamic descriptor and a QSAR study with extended steroid benchmark dataset

Journal of Computer-aided Molecular Design
K A TuppurainenReino Laatikainen

Abstract

The role of intramolecular motions in ligand-macromolecule interactions has been explored by developing and validating ALPHA, a novel QSAR (quantitative structure-activity relationship) descriptor. It is based on the spectral exponents (alpha), which measure the degree of 1/f alpha noise of coordinate fluctuations in molecular dynamics (MD) simulations. ALPHA is the first truly 'dynamic' QSAR descriptor, i.e., it can be derived directly from an MD trajectory. The performance of ALPHA was tested in detail employing the CBG (corticosteroid binding globulin) affinity of 31 benchmark steroids, supplemented with 11 steroids as an external test set. The only fair (42-50%) correlations of ALPHA with static 3D and electronic descriptors mean that ALPHA forms an independent molecular property. Furthermore, inclusion of ALPHA in the SOMFA/ESP model improves the correlation coefficient from 0.86 to 0.91, and /delta/ave from 0.46 to 0.36 for the benchmark dataset. The predictive ability of ALPHA can be interpreted as indirect evidence of the dynamic contribution to ligand-macromolecule interactions. The physical background of ALPHA is discussed and the importance of molecular motions for biological activity is anticipated.

Citations

Jan 24, 2006·SAR and QSAR in Environmental Research·S-P KorhonenM Peräkylä
Aug 30, 2008·Toxicology and Applied Pharmacology·Nels ThorsteinsonGeoffrey L Hammond
Apr 24, 2016·Spectrochimica Acta. Part A, Molecular and Biomolecular Spectroscopy·Andreea-Celia BencheaDana Ortansa Dorohoi
Nov 5, 2016·Journal of Biomolecular Structure & Dynamics·Weilong ZhongJianping Lin
Sep 15, 2010·Journal of Computational Chemistry·Juan DuXiaojun Yao
May 11, 2019·Current Topics in Medicinal Chemistry·Oscar Martínez-SantiagoHai Pham-The

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.