Ab initioLCAO‐MO‐SCF calculation of the electrostatic molecular potential of chlorpromazine and promazine

Abstract

AbstractsThe electrostatic potential V(r) arising from the ab initio LCAO-MO-SCF wave functions of chlorpromazine ( c p z ) and promazine (PZ) has been calculated and discussed. In this approximation, the most probable sites of attack and reaction paths of electrophilic reagents are pointed out and compared. The analysis of V(r) shows that the phenothiazine group has strong nucleophilic properties which are influenced by the phenothiazine substituent and that the electrostatic reactivity of CPZ and PZ is decidedly different near the phenothiazine substituent and similar near the side chain N atom. The dependence of V(r) on the accuracy of the wave function has also been discussed by comparing some ab initio results on pyrrole, pyrazole, and imidazole obtained with a large basis set with an ab initio minimum basis set and with CNDO calculations.Le potentiel Clectrostatique V(r) obtenu par des fonctions d'onde de type LCAO-MO-SCF ab initio pour la chlorpromazine (CPZ) et la promazine (PZ) est discutt. Les sites d'attaque les plus probables et les routes de rtaction de reactants tlectrophiles sont indiquts et comparts. L'analyse de V(r) montre que le groupe phknothiazine a des proprittts nucltophiles fortes, qui sont influendes par le substituant de la phtnothiazine et que les rCactivitts de CPZ et PZ sont remarquablement difftrentes prts du substituant du phtnothiazine mais semblables prts de l'atome d'azote de la chahe de c8tt. On discute aussi la dtpendance de V(r) de la prtcision de la fonction d'onde en comparant quelques rtsultats ab inifio pour le pyrrol, le pyrazole et I'imidazole obtenus avec des jeux de base diffkrents et des rtsultats obtenus par des calculs CNDO.Das von LCAO-MO-SCF-Wellenfunktionen von ab initio-Typ fur Chloropromazin (CPZ) und Promazin (PZ) erhaltene elektrostatische Potential V(r) wird diskutiert. Die wahrscheinlichsten Angriffsplatze und Reaktionspfade elektrophiler Reagenten werden angedeutet und verglichen. Die Analyse von V(r) zeigt, dass die Phenothiazingruppe starke nukleophile Eigenschaften hat, die vom Phenothiazinsubstituent beeinflusst werden und dass die elektrostatischen Reaktivitaten von CPZ und PZ in der Nahe vom Phenothiazinsubstituent ganz verschieden aber in der Nahe vom N-Atom der Seitenkette ahnlich sind. Die Abhangigkeit von V(r) von der Genauigkeit der Wellenfunktion ist auch durch Vergleich einiger abinitio-Ergebnisse mit verschiedenen Basissatzen fur Pyrrol, Pyrazol und Imidazol mit entsprechenden CNDO-Resultaten diskutiert worden.

Molecular Electrostatic Potentials: An Effective Tool for the Elucidation of Biochemical Phenomena

“…tions give relatively good results (first-order accuracy) for properties that are calculated from the electronic density function, as is V(rT) (5-7). Furthermore, extensive investigations have shown that a generally reliable electrostatic potential can be obtained even with self-consistent-field (SCF) wave functions that are not near Hartree-Fock quality (1,(8)(9)(10)(11)(12)(13). V(Fr) is also being determined experimentally to an increasing extent, by diffraction methods (14)(15)(16)(17), but at present the quantum chemical approach remains the more accurate and more practical one.…”

Quantum chemical and physicochemical influences on structure–activity relations and drug design

“…In the rr-region of the ally1 group, only the semiempirical results using the approximation IV and the s~o -6 G expansion are in agreement with the ab initio ones. From these and other results [55,58,61,62] the conclusion remains that the CNDO and INDO methods can only be used with caution to get V(r) and that it seems difficult to derive any general rules.…”

“…The case of requirement of similar maps around the pharmacophoric portions of direct agonists to normal neurotransmitters and the normal neurotransmitters themselves or around the relevant pharmacophoric portions of two related drugs with the same mode of direct action is more stringent than requirements on maps for comparison of agonist and antagonist action. Moreover, to investigate in a thorough and comprehensive manner, the agreement or disagreement of electrostatic molecular potential maps generated from CNDO or INDO wave functions (either orthogonalized or deorthogonalized), to determine the influence of the various approximations when CNDO or INDO wave functions are used and to assess the influence of the GTO expansion to STOS in collaboration with Petronogolo [61] we generated the maps using both approximations I11 and IV and s~o -3 G and s~o -6 G expansions. Striking changes are obtained deorthogonalizing both the CNDO …”

Ab initio and nonempirical MODPOT/VRDDO calculations on drugs, carcinogens, suspected teratogens, and biomolecules

“…Using the criterion we defined above, that two related drugs which exert a common pharmacological effect must generate similar or identical maps around their relevant pharmacologically significant pharmacophores, it was seen that around the N atom in the lone-pair direction relative to the N atom in the morphine and nalorphine molecules, the electrostatic molecular potential contour maps were generated that were almost identical in shape as well as numerical value [41]. Thus, it must be in this direction from the N atom that both the morphine and nalorphine exert their common narcotic agonist effect.…”