A conformational analysis of four N-2-phenyl-(substituted)-guanine (PHG) derivatives, which are herpes simplex virus thymidine kinase inhibitors (HSV TK), was performed mainly with the semiempirical AM1 method. Nonempirical (ab initio) HF and MP2 calculations were employed to refine some of the results obtained with the semiempirical method. The two dihedral angles that connect the phenyl and the guanine rings were varied for systematic conformational search. Four stable conformations were found: C1 (theta(1) = 184 degrees; theta(2) = 58 degrees); C2(theta(1) = 174 degrees; theta(2) = 127 degrees); C3(theta(1) = 186 degrees; theta(2) = 233 degrees) and C4(theta(1) = 176 degrees; theta(2) = 303 degrees), in which theta(1) = N1-C2-N11-C1', and theta(2) = C2-N11-C1'-C2'. The conformation C3 was found to be equivalent to the bioactive conformation proposed in a previous paper. (C) 2000 Elsevier Science B.V, All rights reserved.49893100