Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Bioisosteric replacements and scaffold hopping play an important role in modern drug discovery and design, as they enable the change of either a core scaffold or substitutes in a drug structure, thereby facilitating optimization of pharmacokinetic properties and patenting, while the drug retains its activity. A new knowledge-based method was developed to obtain bioisosteric or scaffold replacements based on the extensive data existing in the Protein Data Bank. The method uses all-against-all ProBiS-based protein superimposition to identify ligand fragments that overlap in similar binding sites and could therefore be considered as bioisosteric replacements. The method was demonstrated on a specific example of drug candidate – a nanomolar butyrylcholinesterase inhibitor, on which bioisosteric replacements of the three ring fragments were performed. The new molecule containing bioisosteric replacements was evaluated virtually using AutoDock Vina; a similar score for the original and the compound with replacements was obtained, suggesting that the newly designed bioisostere compound might retain the potency of the original inhibitor. This work is licensed under a Creative Commons Attribution 4.0 International License

Molecular Surface Walk

A new algorithm to compute a solvent accessible molecular surface (MS) and a graphical computer program for a molecular surface walk have been designed. The surface is generated by rolling a spherical probe representing a solvent molecule over the atoms of the investigated molecule. This surface representation is used in the graphical computer program MS walk to achieve a new way of viewing the molecules. The advantage of the MS walk approach is that the molecular cavities, only partially visible by other methods, can be inspected. The new algorithm’s performance is comparable to that of similar existing algorithms and its time complexity is linear with respect to the number of atoms. The MS algorithm and the MS walk program can be accessed on the Web (http://www.cmm.ki.si/konc/ms_walk)

Molecular Surface Walk

A new algorithm to compute a solvent accessible molecular surface (MS) and a graphical computer program for a molecular surface walk have been designed. The surface is generated by rolling a spherical probe representing a solvent molecule over the atoms of the investigated molecule. This surface representation is used in the graphical computer program MS walk to achieve a new way of viewing the molecules. The advantage of the MS walk approach is that the molecular cavities, only partially visible by other methods, can be inspected. The new algorithm’s performance is comparable to that of similar existing algorithms and its time complexity is linear with respect to the number of atoms. The MS algorithm and the MS walk program can be accessed on the Web (http://www.cmm.ki.si/konc/ms_walk)

ProBiS algorithm for detection of structurally similar protein binding sites by local structural alignment

Motivation: Exploitation of locally similar 3D patterns of physicochemical properties on the surface of a protein for detection of binding sites that may lack sequence and global structural conservation

Genome-wide screening for genetic variants in polyadenylation signal (PAS) sites in mouse selection lines for fatness and leanness

Alternative polyadenylation (APA) determines mRNA stability, localisation, translation and protein function. Several diseases, including obesity, have been linked to APA. Studies have shown that single nucleotide polymorphisms in polyadenylation signals (PAS-SNPs) can influence APA and affect phenotype and disease susceptibility. However, these studies focussed on associations between single PAS-SNP alleles with very large effects and phenotype. Therefore, we performed a genome-wide screening for PAS-SNPs in the polygenic mouse selection lines for fatness and leanness by whole-genome sequencing. The genetic variants identified in the two lines were overlapped with locations of PAS sites obtained from the PolyASite 2.0 database. Expression data for selected genes were extracted from the microarray expression experiment performed on multiple tissue samples. In total, 682 PAS-SNPs were identified within 583 genes involved in various biological processes, including transport, protein modifications and degradation, cell adhesion and immune response. Moreover, 63 of the 583 orthologous genes in human have been previously associated with human diseases, such as nervous system and physical disorders, and immune, endocrine, and metabolic diseases. In both lines, PAS-SNPs have also been identified in genes broadly involved in APA, such as Polr2c, Eif3e and Ints11. Five PAS-SNPs within 5 genes (Car, Col4a1, Itga7, Lat, Nmnat1) were prioritised as potential functional variants and could contribute to the phenotypic disparity between the two selection lines. The developed PAS-SNPs catalogue presents a key resource for planning functional studies to uncover the role of PAS-SNPs in APA, disease susceptibility and fat deposition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00335-022-09967-8

ENZO: A Web Tool for Derivation and Evaluation of Kinetic Models of Enzyme Catalyzed Reactions

We describe a web tool ENZO (Enzyme Kinetics), a graphical interface for building kinetic models of enzyme catalyzed reactions. ENZO automatically generates the corresponding differential equations from a stipulated enzyme reaction scheme. These differential equations are processed by a numerical solver and a regression algorithm which fits the coefficients of differential equations to experimentally observed time course curves. ENZO allows rapid evaluation of rival reaction schemes and can be used for routine tests in enzyme kinetics. It is freely available as a web tool, at http://enzo.cmm.ki.si