Title 
Gridbased Continual Analysis of Molecular Interior for Drug Discovery, QSAR and QSPR


Published in 
Current Drug Discovery Technologies, August 2017

DOI  10.2174/1570163814666170207144018 
Pubmed ID  
Authors 
Andrey V. Potemkin, Maria A. Grishina, Vladimir A. Potemkin 
Abstract 
In 1979, R.D.Cramer and M.Milne made a first realization of the above mentioned principles attempting to compare molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (DYnamic LatticeOriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities. Then, in 1988 the method which was called CoMFA (Comparative Molecular Field Analysis) was introduced and the appropriate software became commercially available. Since 1988, a lot of 3D QSAR methods, algorithms and their modifications are introduced for solving of virtual drug discovery problems (e.g., CoMSIA, CoMMA, HINT, HASL, GOLPE, GRID, PARM, Raptor, BiS, CiS, ConGO,). All the methods can be divided into two groups (classes):1. Methods studying the exterior of molecules; 2) Methods studying the interior of molecules. A series of gridbased computational technologies for Continual Molecular Interior analysis (CoMIn) is invented in the current paper. The gridbased analysis is fulfilled by means of a lattice construction analogously to many other gridbased methods. The further continual elucidation of molecular structure is performed in various ways. (i) In the terms of intermolecular interactions potentials. This can be represented as a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are well known continual functions and their values can be determined in all lattice points for a molecule. (ii) In the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum freeorbital approach AlteQ is proposed. All the functions can be calculated using a quantum approach at a sufficient level of theory and their values can be determined in all lattice points for a molecule. Then, the molecules of a dataset can be superimposed in the lattice for the maximal coincidence (or minimal deviations) of the potentials (i) or the quantum functions (ii). The methods and criteria of the superimposition are discussed. After that a functional relationship between biological activity or property and characteristics of potentials (i) or functions (ii) is created. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page. Therefore, a set of 3D QSAR approaches for continual molecular interior study giving a lot of opportunities for virtual drug discovery, virtual screening and ligandbased drug design is invented. The continual elucidation of molecular structure is performed in the terms of intermolecular interactions potentials and in the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum freeorbital approach AlteQ is proposed. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page. 
Mendeley readers
Geographical breakdown
Country  Count  As % 

Unknown  9  100% 
Demographic breakdown
Readers by professional status  Count  As % 

Researcher  4  44% 
Student > Ph. D. Student  1  11% 
Professor  1  11% 
Student > Doctoral Student  1  11% 
Student > Postgraduate  1  11% 
Other  0  0% 
Unknown  1  11% 
Readers by discipline  Count  As % 

Chemistry  6  67% 
Pharmacology, Toxicology and Pharmaceutical Science  1  11% 
Unknown  2  22% 