Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B(PTP-1B) inhibitors for type 2 diabetes mellitus(T2DM). In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set(34 compounds) and a test set(18 compounds). The highly reliable and predictive 3D-QSAR models were constructed by CoM FA, CoM SIA and topomer Co MFA methods, respectively. The results showed that the cross validated coefficient(q2) and non-cross-validated coefficient(R~2) were 0.554 and 0.999 in the CoM FA model, 0.675 and 0.971 in the CoM SIA model, and 0.628 and 0.939 in the topomer Co MFA model, which suggests that three models are robust and have good exterior predictive capabilities. Furthermore, ten novel inhibitors with much higher inhibitory potency were designed. Our design strategy was that(i) the electronegative substituents(Cl,-CH_2OH, OH and-CH_2Cl) were introduced into the double bond of ring C,(ii) the hydrogen bond acceptor groups(C≡N and N atom), electronegative groups(C≡N, N atom,-COOH and-COOCH_3) and bulky substituents(C_6H_5N) were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors. Oleanolic acid derivatives act as newer protein tyrosine phosphatase 1B (PTP-1B) inhibitors for type 2 diabetes mellitus (T2DM). In order to understand the structural requirement of PTP-1B inhibitors, 52 oleanolic acid derivatives were divided into a training set The highly reliable and predictive 3D-QSAR models were constructed by CoM FA, CoM SIA and topomer Co MFA methods, respectively. The results showed that the cross validated coefficient (q2) and non- Cross-validated coefficients (R ~ 2) were 0.554 and 0.999 in the CoM FA model, 0.675 and 0.971 in the CoM SIA model, and 0.628 and 0.939 in the topomer Co MFA model, which suggests that the three models are robust and have good exterior Our design strategy was that (i) the electronegative substituents (Cl, -CH 2 OH, OH and-CH 2 Cl) were introduced into the double bond of ring C, (ii ) the hydrogen bo nd acceptor groups (C≡N and N atom), electronegative groups (C≡N, N atom, -COOH and-COOCH3) and bulky substituents (C_6H_5N) were connected to the C-3 position, which would result in generating potent and selective PTP-1B inhibitors. We expect that the results in this paper have the potential to facilitate the process of design and to develop new potent PTP-1B inhibitors.