A geometric approach to macromolecule-ligand interactions

doi:10.1016/0022-2836(82)90153-X

Journal of Molecular Biology

Volume 161, Issue 2, 25 October 1982, Pages 269-288

https://doi.org/10.1016/0022-2836(82)90153-X Get rights and content

Abstract

We describe a method to explore geometrically feasible alignments of ligands and receptors of known structure. Algorithms are presented that examine many binding geometries and evaluate them in terms of steric overlap. The procedure uses specific molecular conformations. A method is included for finding putative binding sites on a macromolecular surface.

Results are reported for two systems: the heme-myoglobin interaction and the binding of thyroid hormone analogs to prealbumin. In each case the program finds structures within 1 Å of the X-ray results and also finds distinctly different geometries that provide good steric fits. The approach seems well-suited for generating starting conformations for energy refinement programs and interactive computer graphics routines.

References (30)

D.J. Baker et al.
FEBS Letters
(1981)
C.C.F. Blake et al.
J. Mol. Biol
(1978)
J.M. Cox
J. Mol. Biol
(1967)
R. Potenzone et al.
Computer Chem
(1977)
F.R. Salemme
J. Mol. Biol
(1976)
T. Takano
J. Mol. Biol
(1977)
S.J. Wodak et al.
J. Mol. Biol
(1978)
C.C.F. Blake
C.C.F. Blake et al.
Nature (London)
(1977)
C.C.F. Blake et al.

J.M. Blaney et al.

J. Amer. Chem. Soc

(1982)

J.M. Blaney et al.

J. Med. Chem

(1982)

V. Cody

J. Amer. Chem. Soc

(1974)

M.L. Connolly

Acta Crystallogr

(1982)

Cited by (1967)

Experimental and computational models to understand protein-ligand, metal-ligand and metal-DNA interactions pertinent to targeted cancer and other therapies
2024, European Journal of Medicinal Chemistry Reports
The protein-ligand interactions play critical roles in targeted therapies including viral and cancer therapies. Hence in recent years several experimental and computational methods have been developed to address the mechanism of selectivity, swift binding, and enzyme functions. Furthermore big data, neural networks and artificial intelligence techniques are becoming increasingly important while combinatorial and graph theoretical methods are important arms of such techniques. Experimental methods such as isothermal titration calorimetry and surface plasmon resonance are used frequently to measure the binding affinity. Some of the computational methods used to examine the protein-ligand interactions are electrostatic calculations, molecular dynamics simulation, hybrid dynamics methods, etc., which shed light on structural stability, binding, protein functions etc. In this review we describe applications of a few selected experimental, computational and artificial intelligence tools with focus on graph theory to predict protein-ligand, metal-ligand interactions with implications in various types of malignancies and computational toxicology with focus on protein-heavy metal ion interactions and complexes of heavy metal ions with various ligands of biomedical relevance.
Cannabinoid receptors type 2: Function and development in agonist discovery from synthetic and natural sources with applications for the therapy of osteoporosis
2024, Arabian Journal of Chemistry
Type-2 cannabinoid receptor (CB2R) is a member of the G protein-coupled receptor superfamily with various biological activities in pain regulation, anti-inflammation, anti-fibrosis, and bone metabolism regulation. CB2R modulators have been demonstrated to have significant regulatory effects on bone metabolism with no significant psychoactive adverse effects. In this article, we present a comprehensive review of the molecular mechanism of CB2R in regulating bone metabolism and summarize virtual screening and experimental screening methods for CB2R modulators from natural and synthetic products. Knowing that some botanical compounds are CB2R modulators involved in the regulation of bone metabolism, we also review the botanical and synthetic compounds currently known to be potential CB2R and summarize their regulatory effects on bone metabolism based on the results of animal, osteoblasts (OBs) and osteoclasts (OCs) experimental studies presently available, hoping that the findings and conclusions in this review could provide a scientific basis for the discovery of new CB2R regulators and the development of new anti-osteoporosis drugs.
Understanding the ideal wound healing mechanistic behavior using in silico modelling perspectives: A review
2024, Journal of Tissue Viability
Complexity of the entire body precludes an accurate assessment of the specific contributions of tissues or cells during the healing process, which might be expensive and time consuming. Because of this, controlling the wound's size, depth, and dimensions may be challenging, and there is not yet an efficient and reliable chronic wound model representation. Furthermore, given the inherent challenges associated with conducting non-invasive in vivo investigations, it becomes peremptory to explore alternative methodologies for studying wound healing. In this context, biologically-realistic mathematical and computational models emerge as a valuable framework that can effectively address this need. Therefore, it might improve our approach to understanding the process at its core. This article will examines all facets of wound healing, including the kinds, pathways, and most current developments in wound treatment worldwide, particularly in silico modelling utilizing both mathematical and structure-based modelling techniques. It may be helpful to identify the crucial traits through the feedback loop of computer models and experimental investigations in order to build innovative therapies to cure wounds. Hence the effectiveness of personalised medicine and more targeted therapy in the healing of wounds may be enhanced by this interdisciplinary expertise.
Understanding the contagiousness of Covid-19 strains: A geometric approach
2024, Journal of Molecular Graphics and Modelling
Protein–protein interaction occurs on surface patches with some degree of complementary geometric and chemical features. Building on this understanding, this study endeavors to characterize the spike protein of the SARS-CoV-2 virus at the morphological and geometrical levels in its Alpha, Delta, and Omicron variants. In particular, the affinity between different SARS-CoV-2 spike proteins and the ACE2 receptor present on the membrane of the human respiratory system cells is investigated. To achieve an adequate degree of geometrical accuracy, the 3D depth maps of the proteins in exam are filtered by developing an ad-hoc convolutional filter with a kernel implemented as a sphere of varying radius, simulating a ball rolling on the surface (similar to the 'rolling ball' filter). This ball ideally models a hypothetical molecule that could interface with the protein and is inspired by the geometric approach to macromolecule–ligand interactions proposed by Kuntz et al. in 1982. The aim is to mitigate the imperfections and to obtain a smoother surface that could be studied from a geometrical perspective for binding purposes. A set of geometric descriptors, borrowed from the 3D face analysis context is then mapped point-by-point onto protein depth maps. Following a feature extraction phase inspired by Histogram of Oriented Gradients and Local Binary Patterns, the final histogram features are used as input for a Support Vector Machine classifier to automatically classify the proteins according to their surface affinity, where a similarity in shape is observed between ACE2 and the spike protein of the SARS-CoV-2 Omicron variant. Finally, Root Mean Square Error analysis is used to quantify the geometrical affinity between the ACE2 receptor and the respective Receptor Binding Domains of the three SARS-CoV-2 variants, culminating in a geometrical explanation for the higher contagiousness of Omicron relative to the other variants under study.
Isolation of carminic acid from essential oil, its characterization and applications towards replacing toxic colourants used in soaps
2024, South African Journal of Chemical Engineering
Wide variety of cosmetics was frequently colored using synthetic coloring agents. They were used despite being harmful due to their brightness and exceptional color clarity. Researchers' attention was drawn to recent experiments that substituted natural colorants with harmful ones. We describe how to include (Miss Current) essential oil (EO) into soap using a straight forward saponification process in this article. It is interesting that the essential oil we added made the soap colored. Carminic acid (CA) was the chemical ingredient in soap that produced the color. From EO, carminic acid was extracted as the sodium salt of carminic acid (NCA), and it was then identified using a variety of spectroscopic methods. Infrared (IR) spectroscopy was used to determine the functional groups in CA. Additionally, the presence of carminic acid (CA) was verified using spectroscopic methods using mass and nuclear magnetic resonance (NMR). Additionally, the antibacterial effectiveness of soap with essential oils was assessed. Additionally, molecular docking studies were used to investigate the affinity of carminic acid (CA) for binding to keratin and alpha-amylase.
Spectroscopic (FTIR, FT-Raman, UV–Vis) studies, NMR, NBO analysis, molecular docking studies on 2-cyano-5-fluoropyridine and 3-cyano-2-fluoropyridine
2023, Chemical Physics Impact
In this present work, to investigate the physicochemical properties of the molecules, extensive quantum chemical calculations have been performed on 2-cyano-5-fluoropyridine (2C5FP) and 3-cyano-2-fluoropyridine (3C2FP). Infrared and Raman spectra analysis have been carried out to study the vibrational modes of the molecule. Based on density function theory (DFT) with 6–311 ++ G (d, p) basis set, was also used to compute the same modes. As a result of intramolecular interactions, charge transfer or delocalization of charge has been explained by natural bond orbital analysis. The NMR study was also carried out experimentally and theoretically. The nucleophilic and electrophilic sites were predicted by Molecular Electrostatic Potential surface (MEP). By using the same functional and basis set and GIAO method, theoretical predictions were made. The absorption wavelengths of title molecules have been studied both theoretically and experimentally using UV–visible analysis. The Mullikan population analysis and Natural atomic charges are used to calculate the net charges of the atoms in the molecules, and the calculated net charges are compared to the experimental chemical shift values. A molecular docking study revealed that the title molecules may have antidiabetic properties when bound to protein Glycogen Phosphorylase B Complexed Glucose.

View all citing articles on Scopus

^☆: J.M.B. is supported in part by the American Foundation for Pharmaceutical Education.

View full text

Journal of Molecular Biology

A geometric approach to macromolecule-ligand interactions☆

Abstract

FEBS Letters

J. Mol. Biol

J. Mol. Biol

Computer Chem

J. Mol. Biol

J. Mol. Biol

J. Mol. Biol

Nature (London)

J. Amer. Chem. Soc

J. Med. Chem

J. Amer. Chem. Soc

Acta Crystallogr