COMPUTER GRAPHICS FOR MOLECULAR DESIGN

Abstract: The present invention relates to the identification of substances with certain molecular characteristics, in particular electrostatic potential or ionization energy from selected molecules with supposed desirable properties such as a pharmaceutical activity. Quantum chemical methods such as ab-initio calculations are applied in order to produce approximate wave functions for the molecules. A repeating algorithm can be used to form the wave function and to calculate the equidistant grid points defining the surface of the molecule as an envelope of constant or near constant electron density. Three dimensional graphics of the surface can be used to illustrate these calculated properties. Guided by these graphics the molecule that in the best way corresponds to the desired properties is selected for chemical synthesis.

Description: Computer graphies for molecular design. This iri'ient i on mi l l descr i be α method of designing substαn es «\ i th t its oIecuI or- surface specified desir d moiecuI ar- propert ie , for example electrostatic potential and ionizat ion energy, HoIe uI a surfaces are u uaI Iy des r ibed mith he Ip of the - -an der Uaals model . Hoiueuer this model does not describe the changes in the el ctronic distribut ion that tak place when at ms form 10 molecules. It i i'n tead better to use a surface defined as an en 1 >eIop?ha'jing constant eIectronic ueiιo i •.y _.υrrond ing _iit. mu Iecu 11. This surface does better describe the real electronic density mhich males a molecule unique. \ nouin i ~ that biol ogicaI act i■<e moIecuI es often b i ds to spec i fic If. receptor, in the cells, T > ≡ bi d ding i often an effect ct the receptnr-*. and the molecules complementary forms and complementary quaI i t ies as for e uimoI e eiectrostat i c potent i aI , Posi t i" surfaces on the receptor bind: , to negati" surfaces on the active molecule and "ice uersa. In the same may the average local ioni ation energy described belou) morls, inhere surfaces with a high loni at ion energy bind to surfaces ιuith a low energy according to the theory of eI ctrophi I -nuc I ophi I interact ion. Using the average ionizaion potential on the molecular surface mi ll open a nem possibil ity to study the electrophi l-nuc ieophi I interaction. The first you have to do by industrial designing of a nem drug is to find the part of the cell mhich is the receptor, After thai you ha"e to make a li t of muiecules able to bind to the receptor and ir, that may become a desired biolog ic I ffeet . To clear out the activity of the molecule: you at first must V- synthe ize them. Thi is often π "ery πrduos asl . After that you ha"e to male ests on animals to determine the biological oct ^ t . This i=. πlsn " p f'-u 'T'ensii' and usually toκe a long time. To day you ha e no i nstrument s to determine uuhicn oI ecuIes hauing the best qua I i fiat ions to bind to the receptor, Otherwise you ore able to '. redu e a number of synthezic and development mor only o a fern mo IecuIe , That uiouId Iead to big economic ϊ " fe t for many drug produc ing co panies , It has no«' been shomn that you are able to get a better appl icable U graohicaI picture of oiecuIes and after that Tor ecampIe be abl to adjust them to receptors in a cel l and so on by graphical ly shorn the oiecui e as an en"e iope nau i ng g i"en lectron i c density and to thi 3 ern'eIope bind sμec i fied moIecui or propert ie . C . The invention will be described below, with examples, in the pate claims together with enclosed drawings where figure 1 shows the tert butyl chloride molecule -"- 2 -"- -"- -"- -"- -"- from another "iem -"- 3 -"- -"- methyl chloride molecule -"- 4 -"- -"- tetra chloro dibenzodi OΛine molecule 5 -"- • "- dibenzodio ine molecule and - - o - - - - an 1 1 i ne mo I ecu I e By u ing an ab-initio or a se i e piricaI quanturn chemicaI calculation process you can get an approximate wave function for' any molecule. The surface of the molecule is defined as an enueiope? having constant or near constant electron density, The surface "ill be generated by calcula ing so-called "grid points", hauing equal electron density, For making that you will use a repeated algorithm where the electron density and its graduient in every point is calculated analytically from the wave function. The normal of this surface has in every point the same direction as the graaient of the electron density in this point. The normal becomes consequently by normal isation of the gradient, fit every point of the surface there are a number of molecular properties calculated from the ma" function. Examples or-e : the electrostatic potential the electrostatic field perpendicular to the surface the electrostatic potential polarized by any point charge the HOMO density and the average local ionization energy fil l properties with exception of the a"erage local ionization energy ar-s wel l known and described in the litterature. The a"er ge local ionisat ion energy "1" at the coordinate "r" is defined below: P (r) e )/p (r) "P • )" is the density cont ibution from orbital "i" at V, "p.. " is the density ot the surface (usual ly 0.002 electrons/bohr ), "e " is the orbital energy for orbital "i". The summation is made over all occupied orbitais. Uith help ot computer graphics is the three dimensiona 1 surface displayed color coded accordingly to the value of one of he molecular properties above. Exa ple i. This example will demonstrate how the i ention can be used to predict nucleophi I ic attack. The approach is that surfaces with high electrostatic potential are highly susceptible for- nucleophi lie attack, Three pictures has been produced in a computer- accordinq to the invention, The pictures on the screen has been transferred to three figures., figure 1-3. The colors a\-e of course lost in the bl ck and white p int shown here and thereby or so eof the three dimensional impression lost that do exist when a computer- color screen is U3ed. Figure 1 shows tert butyI chIoride simi I r to the picture. Figure 2 shows also tert butyl chloride but from another direction Figur 3 shows in the same way methyl chloride, The areas marked with haI f-broken lines hπυe a potential higher than +21 kcal/mole, dotted areas have a potential between +21 and 0 kcal mole and ÷dotted areas have a potential below 0 kcal/mole. But tert-butyl chloride is much less reactive towards nucleophi I ic attack due to the steric hinderence at the substiuted carbon. Figure 3 shows methyl cIoride. The coding is the same as for tert- butyI cIoride, Carbon shows a big surface with high electrostat ic potential and is concequent Iy highly sensitive, for a nuclear- attack. Example 2. Figure 4 shows the molecular surface of a tetra chloro- dibenzodioxine molecule, The area with half-broken lines represents an elect os a ic potential on the surface, less than 0 kc l/mol, dotted areas represents a potential between 0 and -10 kcalT ol and +dotted areas below -10 kcal mole, This molecule is known to be highly toxic. Figure 5 -shows the molecular surface of dibenzodioxine coded in the same manner as figure 3. This molecule is rather similar to tetra chloro dibenzodixoine but is not toxic, From the picture is seen that the molecule shows a negative potential on the geater part ...f the surface in contrast to tetra chloro dibenzodioxin. From scient i fic pubI icat ions is Iearned that biological activity of dioxines depends on the electrostatic potential. This example will show that this invention better than other corresponding methods display the di fference between the potent iaI and form of moIecuI s, Example 3, Figure 6 shows the molecular surface of anil in and the average ionisation energy on the surface, The regions marked with half- broken lines have the lowest energy, The tendency of the molecule to transport electrons to an attacking elect ofil is here greatest. That is according to the expe imentally shown picture of anil in as orto-para di ec ing by elcectrophi I ic subst ituton, There is aIso a surface marked with half-broken lines over the free electronic pair of nitrogen. By this function the molecule will become protonized. That is also a kind of nuclear attack. There are no other methods that so clearly point out the electrophi I ic attack sites on a molecule.

Claims: L- i α i ms . I.Uαy of designing substances with on their molecular surfaces 5 speci fied desired propert ies c h a r a c t e r i z e d i n graduaMy seIect ing a number of oIecuIes having probabIy desirabIe properties and on these use an ab-inito or simile^- cuantum chemistry method to get an approximate wave funktion for the molecule in question, use a repeating algorithm or a similar method 1 to f om the wave funkt ion analytically caIcuIate ekvidistant grid points and after that define the surface of the molecule- as an envelope of constant or near constant electronic density, and on this surface with help of three dimensional graphics illustrate the qvantum chemically calculated molecular properties and then select 15> the molecule that in the best way corresponds to the desired propert ies. 2, Hay of designing substances according to clai 1 c h a r a c t e r i z e d i n the fact that the molecular property is the 0 electrostatic potential. 3. Way of designing substances according to claim 1 c h a r a c t e r i z e d i n the fact that the molecular property is the average local ionization energy. 5 4. Hay of designing substances according to claim 1 c h a r a c t e r i z e d b y the fact that the molecular property is the electrostat ical field is pependicuIar to the surface. :.0 5. Way of designing substances according to claim 1 c h a r a c t e r i z e d i n the fact that the moIecuIare property is the HOMO density. 6. Hay of designing substances according to clai 1 c h a r a c t 5 e r i z e d i n the fact that the substance is biological activ. 0 A_l~..'

Inventors: BRINCK NILS TORE, SJOEBERG PER, BRINCK, NILS, TORE, SJOEBERG, PER
Applicants: BRINCK NILS TORE, SJOEBERG PER, BRINCK, NILS, TORE, SJOEBERG, PER
Application year: 1990
Main classification: G01N33
IPC codes: C07K1, G06F17