Novel Radial Distribution Function Approach in the Study of Point Mutations: the HIV-1 Protease Case Study

Abstract

Background: Mutations are one of the engines of evolution. Under constant stress pressure, mutations can lead to the emergence of unwanted, drug resistant entities. Methodology: The radial distribution function weighted by the number of valence shell electrons is used to design quantitative structure–activity relationship (QSAR) model relating descriptors with the inhibition constant for a series of wild-type HIV-1 protease inhibitor complexes. The residuals of complexes with mutant HIV-1 protease were correlated with the energy of the highest occupied molecular orbitals of the residues introduced to enzyme via point mutations. Conclusion: Successful identification of residues Ile3, Asp25, Val32 and Ile50 as the one whose substitution influences the inhibition constant the most, demonstrates the potential of the proposed methodology for the study of the effects of point mutations.

A new glimpse on the active site of SARS-CoV-2 3CLpro, coupled with drug repurposing study

“…Ligands were excluded from calculations, to preserve consistency and for easier similarity index comparison. For more details see References [ 50 , 52 ].…”

“…In this paper, we calculated the recently introduced radial distribution function (RDF) weighted by the number of valence shell electrons [ 50 – 52 ] for 159 experimentally determined structures of SARS-CoV-2 3CLpro complexed with different ligands. The structural advantages of RDF, like it unambiguously describes 3D structures, its independence of the size of a molecule, and being invariant against translation and rotation of a molecule, are upgraded with electronic properties characteristic for each atom in a molecule.…”

The design of compounds with desirable properties – The anti‐HIV case study

“…Descriptors based on the radial distribution function weighted by the number of valence shell electrons were used by Potemkin's group to establish a model relating descriptors with the inhibition constant for a series of HIV‐PR inhibitors 20,23 . Additionally, they exploited those models to study influence of point mutations of HIV‐PR to the inhibition constant 21 . 3D‐QSAR models for thiazolidinones of Ravichandran et al 27 identified the steric and electrostatic properties, as well as the hydrogen bond acceptor, hydrogen bond donor, and hydrophobic properties correlate the most with inhibition potency toward HIV‐1 reverse transcriptase (HIV‐RT).…”

“…[3][4][5] From the perspective of the human immunodeficiency virus, the entity with the highest reported mutation rate, 6 it successfully fights continuous drug selective pressure, leading to the emergence of drug resistant forms. 7 Due to the absence of a successful anti-HIV vaccine and drawbacks of presently approved anti-HIV drugs, a design of a new drug candidates, with increased potency and less side effects (less toxic, increased pharmacokinetic properties) remains hot topic in scientific and pharmaceutical community, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] even 30 years after the first registered drug, azidothymidine. 25 Over the past 20 years, myriad of a quantitative structure-activity relationship (QSAR) studies were performed with the aim to design novel anti-HIV compounds.…”

“…20,23 Additionally, they exploited those models to study influence of point mutations of HIV-PR to the inhibition constant. 21 3D-QSAR models for thiazolidinones of Ravichandran et al 27 identified the steric and electrostatic properties, as well as the hydrogen bond acceptor, hydrogen bond donor, and hydrophobic properties correlate the most with inhibition potency toward HIV-1 reverse transcriptase (HIV-RT). One of the limitations of the most of QSAR studies is that they took into consideration the homogeneous series of compounds against only one protein.…”